Carbamate-substituted oxindole derivatives and use thereof for the treatment of vasopressin-dependent diseases

ABSTRACT

The present invention relates to novel carbamate-substituted oxindole derivatives, pharmaceutical compositions comprising them, and their use for the treatment of vasopressin-dependent disorders.

The present invention relates to novel substituted oxindole derivatives,pharmaceutical compositions comprising them, and their use for thetreatment of vasopressin-dependent disorders.

Vasopressin is an endogenous hormone which exerts various effects onorgans and tissues. It is suspected that the vasopressin system isinvolved in various pathological states such as, for example, heartfailure and high blood pressure. At present, three receptors (V1a, V1bor V3 and V2) via which vasopressin mediates its numerous effects areknown. Antagonists of these receptors are therefore being investigatedas possible new therapeutic approaches for the treatment of diseases (M.Thibonnier, Exp. Opin. Invest. Drugs 1998, 7(5), 729-740).

Novel substituted oxindoles having a phenylsulfonyl group in position 1are described herein. 1-Phenylsulfonyl-1,3-dihydro-2H-indol-2-ones havepreviously been described as ligands of vasopressin receptors. WO93/15051, WO 95/18105, WO 98/25901, WO 01/55130, WO 01/55134, WO01/164668 and WO 01/98295 also describe derivatives having arylsulfonylgroups in position 1 of the oxindole structure. These compounds differfrom the compounds of the invention essentially through the substituentsin position 3.

Thus, WO 93/15051 and WO 98/25901 describe1-phenylsulfonyl-1,3-dihydro-2H-indol-2-ones, in which the oxindolestructure is substituted in position 3 by two alkyl radicals which mayalso together form a cycloalkyl radical (spiro linkage), as ligands ofvasopressin receptors. As alternative, the spiro ring may compriseheteroatoms such as oxygen and nitrogen (optionally with substituents).

WO 95/18105 describes 1-phenylsulfonyl-1,3-dihydro-2H-indol-2-oneshaving a nitrogen atom in position 3 as ligands of vasopressinreceptors. In addition, radicals selected from optionally substitutedalkyl, cycloalkyl, phenyl or benzyl radicals are bonded in position 3.

WO 03/008407 describes 1-phenylsulfonyloxindoles in whichpyridylpiperazines are linked via an oxycarbonyl group to the oxindolein position 3.

WO 2005/030755 describes as example 108 the 2-methoxypyridin-3-ylcarbamate compound5-cyano-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate (according to IUPACnomenclature:5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazin-1-carboxylate).

WO 2006/005609 describes the 2-ethoxyphenyl carbamate compounds1-(2,4-dimethoxy-1-benzenesulfonyl)-5-cyano-2-oxo-3-(2-ethoxyphenyl)-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate (example 63) and5-cyano-1-(2,4-dimethoxybenzenesulfonyl)-3-(2-ethoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate dihydrochloride(example 172).

Besides the binding affinity for the vasopressin V1b receptor, furtherproperties may be advantageous for the treatment and/or prophylaxis ofvasopressin-dependent disorders, such as, for example:

1.) a selectivity for the vasopressin V1b receptor compared with thevasopressin V1a receptor, i.e. the quotient of the binding affinity forthe V1a receptor (Ki(V1a) (determined in the unit “nanomolar (nM)”) andthe binding affinity for the V1b receptor (Ki(V1b)) (determined in theunit “nanomolar (nM)”). A larger quotient Ki(V1a)/Ki(V1b) means agreater V1b selectivity;2.) a selectivity for the vasopressin V1b receptor compared with thevasopressin V2 receptor, i.e. the quotient of the binding affinity forthe V2 receptor (Ki(V2) (determined in the unit “nanomolar (nM)”) andthe binding affinity for the V1b receptor (Ki(V1b)) (determined in theunit “nanomolar (nM)”). A larger quotient Ki(V2)/Ki(V1b) means a greaterV1b selectivity;3.) a selectivity for the vasopressin V1b receptor compared with theoxytocin OT receptor, i.e. the quotient of the binding affinity for theOT receptor (Ki(OT) (determined in the unit “nanomolar (nM)”) and thebinding affinity for the V1b receptor (Ki(V1b)) (determined in the unit“nanomolar (nM)”). A larger quotient Ki(OT)/Ki(V1b) means a greater V1bselectivity.4.) the metabolic stability, for example determined from the half-lives,measured in vitro, in liver microsomes from various species (e.g. rat orhuman);5.) no or only low inhibition of cytochrome P450 (CYP) enzymes:cytochrome P450 (CYP) is the name for a superfamily of heme proteinshaving enzymatic activity (oxidase). They are also particularlyimportant for the degradation (metabolism) of foreign substances such asdrugs or xenobiotics in mammalian organisms. The principalrepresentatives of the types and subtypes of CYP in the human body are:CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g.grapefruit juice, cimetidine, erythromycin) are used at the same time asmedicinal substances which are degraded by this enzyme system and thuscompete for the same binding site on the enzyme, the degradation thereofmay be slowed down and thus effects and side effects of the administeredmedicinal substance may be undesirably enhanced;6.) a suitable solubility in water (in mg/ml);7.) suitable pharmacokinetics (time course of the concentration of thecompound of the invention in plasma or in tissue, for example brain).The pharmacokinetics can be described by the following parameters:half-life, volume of distribution, plasma clearance, AUC (area under thecurve, area under the concentration-time curve), oral bioavailability,the so-called brain-plasma ratio;8.) a suitable portion of the active substance is bound to plasmaproteins (drug-plasma protein binding (PPB) value);9.) no or only low blockade of the hERG channel: compounds which blockthe hERG channel may cause a prolongation of the QT interval and thuslead to serious disturbances of cardiac rhythm (for example so-called“torsade de pointes”). The potential of compounds to block the hERGchannel can be determined by means of the displacement assay withradiolabelled dofetilide which is described in the literature (G. J.Diaz et al., Journal of Pharmacological and Toxicological Methods, 50(2004), 187-199). A smaller IC50 in this dofetilide assay means agreater probability of potent hERG blockade. In addition, the blockadeof the hERG channel can be measured by electrophysiological experimentson cells which have been transfected with the hERG channel, by so-calledwhole-cell patch clamping (G. J. Diaz et al., Journal of Pharmacologicaland Toxicological Methods, 50 (2004), 187-199).

It was therefore an object of the present invention to provide compoundsfor the treatment or prophylaxis of various vasopressin-dependentdiseases. The compounds were intended to have a high activity andselectivity, especially a high affinity and selectivity vis-à-vis thevasopressin V1b receptor. In addition, the substance of the inventionwas intended to have one or more of the aforementioned advantages 1.) to9.).

The object is achieved by compounds of the formula I

in which

-   R¹ is hydrogen, methoxy or ethoxy;-   R² is hydrogen or methoxy;-   R³ is hydrogen, methyl, ethyl, n-propyl or isopropyl;-   X¹ and X² are N or CH, with the proviso that X¹ and X² are not    simultaneously N;    and by their pharmaceutically acceptable salts and prodrugs thereof.

Accordingly, the present invention relates to compounds of the formula I(also “compounds I” hereinafter) and the pharmaceutically acceptablesalts of the compounds I and the prodrugs of the compounds I.

The pharmaceutically acceptable salts of compounds of the formula I,which are also referred to as physiologically tolerated salts, areordinarily obtainable by reacting the free base of the compounds I ofthe invention (i.e. of the compounds I according to structural formulaI) with suitable acids. Examples of suitable acids are listed in“Fortschritte der Arzneimittelforschung”, 1966, Birkhäuser Verlag, vol.10, pp. 224-285. These include for example hydrochloric acid, citricacid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid,acetic acid, formic acid, maleic acid and fumaric acid.

The term “prodrugs” means compounds which are metabolized in vivo to thecompounds I of the invention. Typical examples of prodrugs are describedin C. G. Wermeth (editor): The Practice of Medicinal Chemistry, AcademicPress, San Diego, 1996, pages 671-715. These include for examplephosphates, carbamates, amino acids, esters, amides, peptides, ureas andthe like. Suitable prodrugs in the present case may be for examplecompounds I in which the outer nitrogen atom of the outerpiperidine/piperazine ring forms an amide/peptide linkage by thisnitrogen atom being substituted by a C₁-C₄-alkylcarbonyl group, e.g. byacetyl, propionyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonylor tert-butylcarbonyl (pivaloyl), by benzoyl, or by an amino acidresidue linked via CO, e.g. glycine, alanine, serine, phenylalanine andthe like linked via CO, in the position of the radical R³. Furthersuitable prodrugs are alkylcarbonyloxyalkyl carbamates in which theouter nitrogen atom of the outer piperidine/piperazine ring has in theposition of the radical R³ a group of the formula—C(═O)—O—CHR^(a)—O—C(═O)—R^(b) in which R^(a) and R^(b) areindependently of one another C₁-C₄-alkyl. Such carbamates are describedfor example in J. Alexander, R. Cargill, S. R. Michelson, H. Schwam, J.Medicinal Chem. 1988, 31(2), 318-322. These groups can then beeliminated under metabolic conditions and result in compounds I in whichR³ is H.

C₁-C₄-Alkyl is in the context of the present invention a linear orbranched alkyl radical having 1 to 4 carbon atoms, such as methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

C₁-C₃-Alkoxy is in the context of the present invention a linear orbranched alkyl radical linked via an oxygen atom and having 1 to 3carbon atoms. Examples are methoxy, ethoxy, n-propoxy and isopropoxy.

The compounds of the invention of the formula I, their pharmacologicallyacceptable salts and their prodrugs may also be present in the form ofsolvates or hydrates. Solvates mean in the context of the presentinvention crystalline forms of the compounds I or of theirpharmaceutically acceptable salts or prodrugs thereof which comprisesolvent molecules incorporated in the crystal lattice. The solventmolecules are preferably incorporated in stoichiometric ratios. Hydratesare a specific form of solvates; the solvent in this case is water.

The statements made hereinafter concerning suitable and preferredfeatures of the invention, especially concerning the variables R¹, R²,R³, X¹ and X² in the compound I, but also concerning the features of theprocess of the invention and of the use according to the invention applyboth taken on their own and preferably in any possible combination withone another.

The compounds I are preferably provided in the form of the free base(i.e. according to structural formula I) or in the form of their acidaddition salts.

In a preferred embodiment, R¹ is hydrogen or methoxy.

In a particularly preferred embodiment, R¹ and R² are both H.

In an alternatively preferred embodiment, R¹ is methoxy and R² is H.

In an alternatively particularly preferred embodiment, R¹ is H and R² ismethoxy.

In an alternatively particularly preferred embodiment, R¹ and R² areboth methoxy.

In a further preferred embodiment, R³ is hydrogen, methyl or ethyl.

In a further preferred embodiment, one of the variables X¹, X² is N andthe other is CH.

In a particularly preferred embodiment in this connection, X¹ is N andX² is CH.

In an alternatively particularly preferred embodiment, X¹ is CH and X²is N.

The invention preferably relates to compounds of the formula I in which

-   R¹ is hydrogen or methoxy;-   R² is hydrogen or methoxy;-   R³ is hydrogen, methyl, ethyl, n-propyl or isopropyl, preferably    hydrogen, methyl or ethyl;-   X¹ is N or CH;-   X² is N or CH;    where X¹ and X² are not simultaneously N;    and the pharmaceutically acceptable salts and prodrugs thereof.

In a particular embodiment, one of the variables X¹ or X² is N and theother is CH.

The invention particularly preferably relates to compounds of theformula I in which

-   R¹ is hydrogen or methoxy;-   R² is hydrogen or methoxy;-   R³ is hydrogen, methyl or ethyl;-   X¹ is N;-   X² is CH;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention alternatively particularly preferably relates to compoundsof the formula I in which

-   R¹ is hydrogen or methoxy;-   R² is hydrogen or methoxy;-   R³ is hydrogen, methyl or ethyl;-   X¹ is CH;-   X² is N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention further particularly preferably relates to compounds ofthe formula I in which

-   R¹ is hydrogen or methoxy;-   R² is hydrogen or methoxy;-   R³ is hydrogen, methyl or ethyl;-   X¹ is CH;-   X² is CH;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention particularly relates to compounds of the formula I inwhich

-   R¹ is methoxy;-   R² is methoxy;-   R³ is hydrogen, methyl or ethyl, preferably methyl or ethyl;-   X¹ is CH;-   X² is N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention furthermore particularly relates to compounds of theformula I in which

-   R¹ is hydrogen;-   R² is methoxy;-   R³ is hydrogen, methyl or ethyl, preferably methyl or ethyl;-   X¹ is CH;-   X² is N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention furthermore particularly relates to compounds of theformula I in which

-   R¹ is methoxy;-   R² is hydrogen;-   R³ is hydrogen, methyl or ethyl, preferably methyl or ethyl;-   X¹ is CH;-   X² is N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention furthermore preferably relates to compounds of the formulaI in which

-   R¹ is hydrogen;-   R² is hydrogen;-   R³ is hydrogen, methyl or ethyl, preferably methyl or ethyl;-   X¹ is CH;-   X² is N;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention furthermore particularly relates to compounds of theformula I in which

-   R¹ is methoxy;-   R² is methoxy;-   R³ is hydrogen, methyl or ethyl, preferably methyl or ethyl;-   X¹ is N;-   X² is CH;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention furthermore particularly relates to compounds of theformula I in which

-   R¹ is hydrogen;-   R² is methoxy;-   R³ is hydrogen, methyl or ethyl, preferably methyl or ethyl;-   X¹ is N;-   X² is CH;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention furthermore particularly relates to compounds of theformula I in which

-   R¹ is methoxy;-   R² is hydrogen;-   R³ is hydrogen, methyl or ethyl, preferably methyl or ethyl;-   X¹ is N;-   X² is CH;    and the pharmaceutically acceptable salts and prodrugs thereof.

The invention furthermore particularly relates to compounds of theformula I in which

-   R¹ is hydrogen;-   R² is hydrogen;-   R³ is hydrogen, methyl or ethyl, preferably methyl or ethyl;-   X¹ is N;-   X² is CH;    and the pharmaceutically acceptable salts and prodrugs thereof.

Examples of preferred embodiment of the present invention are compoundsof the formula I and the pharmaceutically acceptable salts and prodrugsthereof, in which the radicals X¹, X², R¹, R² and R³ assume in each casethe meanings mentioned in each line in the following table 1.

TABLE 1 Example No. X¹ X² R¹ R² R³ 1 N CH Methoxy Methoxy Methyl 2 N CHMethoxy H Methyl 3 N CH Ethoxy H Methyl 4 N CH H H Methyl 5 N CH HMethoxy Methyl 6 N CH Ethoxy Methoxy Methyl 7 N CH Methoxy Methoxy Ethyl8 N CH Methoxy H Ethyl 9 N CH Ethoxy H Ethyl 10 N CH H H Ethyl 11 N CH HMethoxy Ethyl 12 N CH Ethoxy Methoxy Ethyl 13 N CH Methoxy Methoxyn-Propyl 14 N CH Methoxy H n-Propyl 15 N CH Ethoxy H n-Propyl 16 N CH HH n-Propyl 17 N CH H Methoxy n-Propyl 18 N CH Ethoxy Methoxy n-Propyl 19N CH Methoxy Methoxy Isopropyl 20 N CH Methoxy H Isopropyl 21 N CHEthoxy H Isopropyl 22 N CH H H Isopropyl 23 N CH H Methoxy Isopropyl 24N CH Ethoxy Methoxy Isopropyl 25 N CH Methoxy Methoxy H 26 N CH MethoxyH H 27 N CH Ethoxy H H 28 N CH H H H 29 N CH H Methoxy H 30 N CH EthoxyMethoxy H 31 CH N Methoxy Methoxy Methyl 32 CH N Methoxy H Methyl 33 CHN Ethoxy H Methyl 34 CH N H H Methyl 35 CH N H Methoxy Methyl 36 CH NEthoxy Methoxy Methyl 37 CH N Methoxy Methoxy Ethyl 38 CH N Methoxy HEthyl 39 CH N Ethoxy H Ethyl 40 CH N H H Ethyl 41 CH N H Methoxy Ethyl42 CH N Ethoxy Methoxy Ethyl 43 CH N Methoxy Methoxy n-Propyl 44 CH NMethoxy H n-Propyl 45 CH N Ethoxy H n-Propyl 46 CH N H H n-Propyl 47 CHN H Methoxy n-Propyl 48 CH N Ethoxy Methoxy n-Propyl 49 CH N MethoxyMethoxy Isopropyl 50 CH N Methoxy H Isopropyl 51 CH N Ethoxy H Isopropyl52 CH N H H Isopropyl 53 CH N H Methoxy Isopropyl 54 CH N Ethoxy MethoxyIsopropyl 55 CH N Methoxy Methoxy H 56 CH N Methoxy H H 57 CH N Ethoxy HH 58 CH N H H H 59 CH N H Methoxy H 60 CH N Ethoxy Methoxy H 61 CH CHMethoxy Methoxy Methyl 62 CH CH Methoxy H Methyl 63 CH CH Ethoxy HMethyl 64 CH CH H H Methyl 65 CH CH H Methoxy Methyl 66 CH CH EthoxyMethoxy Methyl 67 CH CH Methoxy Methoxy Ethyl 68 CH CH Methoxy H Ethyl69 CH CH Ethoxy H Ethyl 70 CH CH H H Ethyl 71 CH CH H Methoxy Ethyl 72CH CH Ethoxy Methoxy Ethyl 73 CH CH Methoxy Methoxy n-Propyl 74 CH CHMethoxy H n-Propyl 75 CH CH Ethoxy H n-Propyl 76 CH CH H H n-Propyl 77CH CH H Methoxy n-Propyl 78 CH CH Ethoxy Methoxy n-Propyl 79 CH CHMethoxy Methoxy Isopropyl 80 CH CH Methoxy H Isopropyl 81 CH CH Ethoxy HIsopropyl 82 CH CH H H Isopropyl 83 CH CH H Methoxy Isopropyl 84 CH CHEthoxy Methoxy Isopropyl 85 CH CH Methoxy Methoxy H 86 CH CH Methoxy H H87 CH CH Ethoxy H H 88 CH CH H H H 89 CH CH H Methoxy H 90 CH CH EthoxyMethoxy H

The compounds I of the invention have a center of chirality in position3 of the 2-oxindole ring. The compounds of the invention may thereforebe in the form of a 1:1 mixture of enantiomers (racemate) or of anonracemic mixture of enantiomers in which one of the two enantiomers,either the enantiomer which rotates the plane of vibration of linearlypolarized light to the left (i.e. minus rotation) (hereinafter (−)enantiomer) or the enantiomer which rotates the plane of vibration oflinearly polarized light to the right (i.e. plus rotation) (hereinafter(+) enantiomer), is enriched, or of substantially enantiopure compounds,that is to say of substantially enantiopure (−) enantiomer or (+)enantiomer. Since the compounds of the invention have a single center ofasymmetry and no axis/plane of chirality, a nonracemic mixture can alsobe defined as a mixture of enantiomers in which either the R or the Senantiomer predominates. Substantially enantiopure compounds canaccordingly also be defined as substantially enantiopure R enantiomer orsubstantially enantiopure S enantiomer.

“Substantially enantiopure compounds” means in the context of thepresent invention those compounds having an enantiomeric excess (ee; %ee=(R−S)/(R+S)×100 or (S−R)/(S+R)×100) of at least 80% ee, preferably atleast 85% ee, more preferably at least 90% ee, even more preferably atleast 95% ee and in particular at least 98% ee.

In one embodiment of the invention, the compounds of the invention arein the form of substantially enantiopure compounds. Particularlypreferred compounds have an enantiomeric excess of at least 85% ee, morepreferably of at least 90% ee, even more preferably of at least 95% eeand in particular of at least 98% ee.

The invention thus relates both to the pure enantiomers and to mixturesthereof, e.g. mixtures in which one enantiomer is present in enrichedform, but also to the racemates. The invention also relates to thepharmaceutically acceptable salts and the prodrugs of the pureenantiomers of compounds I, and the mixtures of enantiomers in the formof the pharmaceutically acceptable salts and prodrugs of compounds I.

Preferred embodiments of the invention are compounds of the formula I asdetailed above which are characterized in that they are in opticallyactive form, and the enantiomer of the relevant compound of the formulaI is the one which rotates the plane of vibration of polarized light tothe left (i.e. minus rotation), in the form of a free base, or apharmaceutically acceptable salt or a prodrug thereof. The enantiomerswith levorotation or minus rotation of the compounds I are also referredto hereinafter as (−) enantiomers.

The statements made in the context of the present invention concerningthe direction of rotation of polarized light relate preferably to thesigns [(+) or (−)] as determined in chloroform as solvent or inchloroform-containing solvent mixtures, in particular in chloroform.

Preferred embodiments of the invention are those compounds of theformula I as detailed above which are characterized in that they are inoptically active form, with the absolute configuration at the chiral C-3ring carbon atom of the oxindole structure corresponding to the absoluteconfiguration at C-3 of the (−) enantiomer of the compound5-cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate (=compound ofexample 1) in the form of the free base. This configuration is alsoreferred to hereinafter as the “preferred configuration”.

Particular preference is given to compounds of the general formula I,pharmaceutically acceptable salts and their prodrugs as detailed abovein which the corresponding (−) enantiomer is present in an opticalpurity (enantiomeric excess, ee) of more than 50% ee, particularlypreferably of at least 80% ee, more preferably of at least 90% ee andeven more preferably of at least 95% ee and in particular of at least98% ee.

Particular preference is alternatively given to compounds of the generalformula I, their pharmaceutically acceptable salts and their prodrugs inwhich the enantiomer displaying the preferred absolute configuration atthe C-3 ring carbon atom is present in with an optical purity(enantiomeric excess, ee) of more than 50% ee, preferably of at least80% ee, more preferably of at least 90% ee, even more preferably of atleast 95% ee and in particular of at least 98% ee.

Likewise preferred embodiments of the invention are compounds of thegeneral formula I as detailed above which are characterized in that theyare in optically inactive form, i.e. in the form of the racemate, or inthe form of a pharmaceutically acceptable salt or of a prodrug of theracemate.

Examples of particularly preferred compounds I are the compounds listedin following table 2 with the example numbers 1 to 90B, and thepharmaceutically acceptable salts and prodrugs thereof. In thisconnection, examples 1 to 90 correspond to the racemate of therespective compounds, the examples with an appended letter “A” (1A, 2A,. . . to 90A) correspond to the dextrorotatory (+) enantiomer and theexamples with an appended letter “B” (1B, 2B, . . . to 90B) correspondto the levorotatory (−) enantiomer of the respective compound 1 to 90.The naming of the compounds corresponds to the naming generated by theACD-Labs version 8.00 release product version 8.05.

TABLE 2 Example No. X¹ X² R¹ R² R³ IUPAC Name  1 N CH Methoxy MethoxyMethyl(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate  1A N CH MethoxyMethoxy Methyl(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate  1B N CH MethoxyMethoxy Methyl(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate  2 N CH Methoxy HMethyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 2A N CH Methoxy H Methyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 2B N CH Methoxy H Methyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 3 N CH Ethoxy H Methyl(±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 3A N CH Ethoxy H Methyl(+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 3B N CH Ethoxy H Methyl(−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 4 N CH H H Methyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate  4A N CH HH Methyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate  4B N CH HH Methyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate  5 N CH HMethoxy Methyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 5A N CH H Methoxy Methyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 5B N CH H Methoxy Methyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 6 N CH Ethoxy Methoxy Methyl(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate  6A N CH Ethoxy Methoxy Methyl(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate  6B N CH Ethoxy Methoxy Methyl(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate  7 N CH Methoxy Methoxy Ethyl(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate  7A N CH MethoxyMethoxy Ethyl(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate  7B N CH MethoxyMethoxy Ethyl(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate  8 N CH Methoxy HEthyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate 8A N CH Methoxy H Ethyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate 8B N CH Methoxy H Ethyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate 9 N CH Ethoxy H Ethyl(±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate 9A N CH Ethoxy H Ethyl(+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate 9B N CH Ethoxy H Ethyl(−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate10 N CH H H Ethyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate 10A N CH HH Ethyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate 10B N CH HH Ethyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate 11 N CH HMethoxy Ethyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate11A N CH H Methoxy Ethyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate11B N CH H Methoxy Ethyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate12 N CH Ethoxy Methoxy Ethyl(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate 12A N CH EthoxyMethoxy Ethyl(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate 12B N CH EthoxyMethoxy Ethyl(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate 13 N CH MethoxyMethoxy n-Propyl(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate 13A N CH MethoxyMethoxy n-Propyl(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate 13B N CH MethoxyMethoxy n-Propyl(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate 14 N CH Methoxy Hn-Propyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate14A N CH Methoxy H n-Propyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate14B N CH Methoxy H n-Propyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate15 N CH Ethoxy H n-Propyl(±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate15A N CH Ethoxy H n-Propyl(+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate15B N CH Ethoxy H n-Propyl(−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate16 N CH H H n-Propyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate 16A N CH HH n-Propyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate 16B N CH HH n-Propyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate 17 N CH HMethoxy n-Propyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate17A N CH H Methoxy n-Propyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate17B N CH H Methoxy n-Propyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate18 N CH Ethoxy Methoxy n-Propyl(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate 18A N CH Ethoxy Methoxy n-Propyl(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate 18B N CH Ethoxy Methoxy n-Propyl(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-propylpiperidin-4-yl)piperazine-1-carboxylate 19 N CH Methoxy Methoxy Isopropyl(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 19A N CH MethoxyMethoxy Isopropyl(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 19B N CH MethoxyMethoxy Isopropyl(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 20 N CH Methoxy HIsopropyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 20A N CH Methoxy HIsopropyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 20B N CH Methoxy HIsopropyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 21 N CH Ethoxy HIsopropyl(±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 21A N CH Ethoxy HIsopropyl(+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 21B N CH Ethoxy HIsopropyl(−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 22 N CH H HIsopropyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 22A NCH H H Isopropyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 22B NCH H H Isopropyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 23 N CHH Methoxy Isopropyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 23A N CH H MethoxyIsopropyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 23B N CH H MethoxyIsopropyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 24 N CH EthoxyMethoxy Isopropyl(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 24A N CH Ethoxy Methoxy Isopropyl(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 24B N CH Ethoxy Methoxy Isopropyl(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(1-isopropylpiperidin-4-yl)piperazine-1-carboxylate 25 N CH Methoxy Methoxy H(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate 25A NCH Methoxy Methoxy H(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate 25B NCH Methoxy Methoxy H(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate 26 NCH Methoxy H H(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate 26A N CHMethoxy H H(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate 26B N CHMethoxy H H(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate 27 N CHEthoxy H H(±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate 27A N CHEthoxy H H(+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate 27B N CHEthoxy H H(−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate 28 N CH HH H(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate 28A N CH H H H(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate 28B N CH H H H(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate 29 N CH H Methoxy H(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate 29A N CHH Methoxy H(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate 29B N CHH Methoxy H(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate 30 N CHEthoxy Methoxy H(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate30A N CH Ethoxy Methoxy H(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate30B N CH Ethoxy Methoxy H(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate31 CH N Methoxy Methoxy Methyl(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate31A CH N Methoxy Methoxy Methyl(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate31B CH N Methoxy Methoxy Methyl(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperidin-4-ylpiperazine-1-carboxylate32 CH N Methoxy H Methyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate32A CH N Methoxy H Methyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate32B CH N Methoxy H Methyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate33 CH N Ethoxy H Methyl(±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate33A CH N Ethoxy H Methyl(+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate33B CH N Ethoxy H Methyl(−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate34 CH N H H Methyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate 34A CH N HH Methyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate 34B CH N HH Methyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate 35 CH N HMethoxy Methyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate35A CH N H Methoxy Methyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate35B CH N H Methoxy Methyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate36 CH N Ethoxy Methoxy Methyl(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate 36A CH N Ethoxy Methoxy Methyl(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate 36B CH N Ethoxy Methoxy Methyl(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate 37 CH N Methoxy Methoxy Ethyl(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate 37A CH N MethoxyMethoxy Ethyl(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate 37B CH N MethoxyMethoxy Ethyl(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate 38 CH N Methoxy HEthyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate38A CH N Methoxy H Ethyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate38B CH N Methoxy H Ethyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate39 CH N Ethoxy H Ethyl(±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate39A CH N Ethoxy H Ethyl(+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate39B CH N Ethoxy H Ethyl(−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate40 CH N H H Ethyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate 40A CH N HH Ethyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate 40B CH N HH Ethyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate 41 CH N HMethoxy Ethyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate41A CH N H Methoxy Ethyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate41B CH N H Methoxy Ethyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate42 CH N Ethoxy Methoxy Ethyl(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate 42A CH N EthoxyMethoxy Ethyl(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate 42B CH N EthoxyMethoxy Ethyl(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate 43 CH N MethoxyMethoxy n-Propyl(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate 43A CH N MethoxyMethoxy n-Propyl(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate 43B CH N MethoxyMethoxy n-Propyl(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate 44 CH N Methoxy Hn-Propyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate44A CH N Methoxy H n-Propyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate44B CH N Methoxy H n-Propyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate45 CH N Ethoxy H n-Propyl(±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate45A CH N Ethoxy H n-Propyl(+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate45B CH N Ethoxy H n-Propyl(−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate46 CH N H H n-Propyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate 46A CH N HH n-Propyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate 46B CH N HH n-Propyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate 47 CH N HMethoxy n-Propyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate47A CH N H Methoxy n-Propyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate47B CH N H Methoxy n-Propyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate48 CH N Ethoxy Methoxy n-Propyl(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate 48A CH N Ethoxy Methoxy n-Propyl(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate 48B CH N Ethoxy Methoxy n-Propyl(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-propylpiperazin-1-yl)piperidine-1-carboxylate 49 CH N Methoxy Methoxy Isopropyl(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 49A CH N MethoxyMethoxy Isopropyl(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 49B CH N MethoxyMethoxy Isopropyl(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 50 CH N Methoxy HIsopropyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 50A CH N Methoxy HIsopropyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 50B CH N Methoxy HIsopropyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 51 CH N Ethoxy HIsopropyl(±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 51A CH N Ethoxy HIsopropyl(+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 51B CH N Ethoxy HIsopropyl(−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 52 CH N H HIsopropyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 52A CHN H H Isopropyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 52B CHN H H Isopropyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 53 CH NH Methoxy Isopropyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 53A CH N H MethoxyIsopropyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 53B CH N H MethoxyIsopropyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 54 CH N EthoxyMethoxy Isopropyl(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 54A CH N Ethoxy Methoxy Isopropyl(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 54B CH N Ethoxy Methoxy Isopropyl(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-(4-isopropylpiperazin-1-yl)piperidine-1-carboxylate 55 CH N Methoxy Methoxy H(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate 55ACH N Methoxy Methoxy H(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate 55BCH N Methoxy Methoxy H(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate 56 CHN Methoxy H H(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate 56A CH NMethoxy H H(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate 56B CH NMethoxy H H(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate 57 CH NEthoxy H H(±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate 57A CH NEthoxy H H(+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate 57B CH NEthoxy H H(−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate 58 CH N HH H(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate 58A CH N H H H(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate 58B CH N H H H(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate 59 CH N H Methoxy H(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate 59A CH NH Methoxy H(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate 59B CH NH Methoxy H(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate 60 CH NEthoxy Methoxy H(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate60A CH N Ethoxy Methoxy H(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate60B CH N Ethoxy Methoxy H(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4-piperazin-1-ylpiperidine-1-carboxylate61 CH CH Methoxy Methoxy Methyl(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate 61ACH CH Methoxy Methoxy Methyl(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate 61BCH CH Methoxy Methoxy Methyl(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate 62CH CH Methoxy H Methyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate 62A CHCH Methoxy H Methyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate 62B CHCH Methoxy H Methyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate 63 CH CHEthoxy H Methyl(±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate 63A CHCH Ethoxy H Methyl(+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate 63B CHCH Ethoxy H Methyl(−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate 64 CH CHH H Methyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate 64A CH CH H HMethyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate 64B CH CH H HMethyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate 65 CH CH H MethoxyMethyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate 65A CHCH H Methoxy Methyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate 65B CHCH H Methoxy Methyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate 66 CH CHEthoxy Methoxy Methyl(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate66A CH CH Ethoxy Methoxy Methyl(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate66B CH CH Ethoxy Methoxy Methyl(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-methyl-4,4′-bipiperidine-1-carboxylate67 CH CH Methoxy Methoxy Ethyl(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate 67ACH CH Methoxy Methoxy Ethyl(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate 67BCH CH Methoxy Methoxy Ethyl(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate 68 CHCH Methoxy H Ethyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate 68A CH CHMethoxy H Ethyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate 68B CH CHMethoxy H Ethyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate 69 CH CHEthoxy H Ethyl(±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate 69A CH CHEthoxy H Ethyl(+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate 69B CH CHEthoxy H Ethyl(−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate 70 CH CHH H Ethyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate 70A CH CH H H Ethyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate 70B CH CH H H Ethyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate 71 CH CH H MethoxyEthyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate 71A CH CHH Methoxy Ethyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate 71B CH CHH Methoxy Ethyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate 72 CH CHEthoxy Methoxy Ethyl(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate72A CH CH Ethoxy Methoxy Ethyl(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate72B CH CH Ethoxy Methoxy Ethyl(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-ethyl-4,4′-bipiperidine-1-carboxylate73 CH CH Methoxy Methoxy n-Propyl(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate 73ACH CH Methoxy Methoxy n-Propyl(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate 73BCH CH Methoxy Methoxy n-Propyl(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate 74CH CH Methoxy H n-Propyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate 74A CHCH Methoxy H n-Propyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate 74B CHCH Methoxy H n-Propyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate 75 CH CHEthoxy H n-Propyl(±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate 75A CHCH Ethoxy H n-Propyl(+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate 75B CHCH Ethoxy H n-Propyl(−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate 76 CH CHH H n-Propyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate 76A CH CH H Hn-Propyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate 76B CH CH H Hn-Propyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate 77 CH CH H Methoxyn-Propyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate 77A CHCH H Methoxy n-Propyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate 77B CHCH H Methoxy n-Propyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate 78 CH CHEthoxy Methoxy n-Propyl(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate78A CH CH Ethoxy Methoxy n-Propyl(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate78B CH CH Ethoxy Methoxy n-Propyl(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-propyl-4,4′-bipiperidine-1-carboxylate79 CH CH Methoxy Methoxy Isopropyl(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate79A CH CH Methoxy Methoxy Isopropyl(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate79B CH CH Methoxy Methoxy Isopropyl(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate80 CH CH Methoxy H Isopropyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate 80ACH CH Methoxy H Isopropyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate 80BCH CH Methoxy H Isopropyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate 81 CHCH Ethoxy H Isopropyl(±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate 81ACH CH Ethoxy H Isopropyl(+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate 81BCH CH Ethoxy H Isopropyl(−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate 82 CHCH H H Isopropyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate 82A CH CH H HIsopropyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate 82B CH CH H HIsopropyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate 83 CH CH HMethoxy Isopropyl(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate 83ACH CH H Methoxy Isopropyl(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate 83BCH CH H Methoxy Isopropyl(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 1′-isopropyl-4,4′-bipiperidine-1-carboxylate 84 CHCH Ethoxy Methoxy Isopropyl(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl1′-isopropyl-4,4′-bipiperidine-1-carboxylate 84A CH CH Ethoxy MethoxyIsopropyl(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl1′-isopropyl-4,4′-bipiperidine-1-carboxylate 84B CH CH Ethoxy MethoxyIsopropyl(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl1′-isopropyl-4,4′-bipiperidine-1-carboxylate 85 CH CH Methoxy Methoxy H(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 85A CH CHMethoxy Methoxy H(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 85B CH CHMethoxy Methoxy H(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 86 CH CHMethoxy H H(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 86A CH CH MethoxyH H(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 86B CH CH MethoxyH H(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 87 CH CH Ethoxy HH(±)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 87A CH CH Ethoxy HH(+)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 87B CH CH Ethoxy HH(−)-5-Cyano-1-[(2-ethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 88 CH CH H H H(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 88A CH CH H H H(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 88B CH CH H H H(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 89 CH CH H Methoxy H(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 89A CH CH HMethoxy H(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 89B CH CH HMethoxy H(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 90 CH CH EthoxyMethoxy H(±)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 90A CH CHEthoxy Methoxy H(+)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate 90B CH CHEthoxy Methoxy H(−)-5-Cyano-1-[(2-ethoxy-4-methoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl 4,4′-bipiperidine-1-carboxylate

Among these, particular preference is given to the racemates (i.e.compounds 1, 2, . . . 90) and their physiologically tolerated salts, andtheir prodrugs. Also particularly preferred are the (−) enantiomers(i.e. compounds 1B, 2B, . . . 90B) and their physiologically toleratedsalts, and their prodrugs. The aforementioned compounds are provided inparticular in the form of their free base or in the form of their acidaddition salts.

Examples of synthetic routes for preparing the oxindole derivatives ofthe invention are described below.

The oxindoles of the invention can be prepared in various ways, and thepreparation is outlined in synthesis schemes 1 and 2. The variables inthese synthetic schemes have the same meanings as in formula I.

The 3-hydroxy-1,3-dihydroindol-2-ones IV can be obtained by addition ofmetallated heterocycles III onto the 3-keto group of the isatins II. Themetallated heterocycles, such as, for example, the correspondingGrignard (Mg) or organyllithium compound, can be obtained in anyconventional way from halogen or hydrocarbon compounds. Examples ofmethods are present in Houben-Weyl, Methoden der Organischen Chemie,vol. 13, 1-2, chapter on Mg and Li compounds. The isatins II are eithercommercially available or can be prepared in analogy to methodsdescribed in the literature (Advances in Heterocyclic Chemistry, A. R.Katritzky and A. J. Boulton, Academic Press, New York, 1975, 18, 2-58;J. Brazil. Chem. Soc. 12, 273-324, 2001).

The 3-hydroxyoxindoles IV which contain for example in position 5 aniodine as radical R^(a) in the 6-membered aromatic can be converted withKCN or Zn(CN)₂ with Pd(0) catalysis in solvents such asdimethylformamide or tetrahydrofuran and, where appropriate also withthe addition of bases such as K₂CO₃ or other carbonates or amines, atelevated temperature into the analogous cyan-containing3-hydroxyoxindole IV. It is possible to take as Pd(0) salts for exampletransition metal complexes prepared in situ from PdCl₂ or PdOAc₂ byadding phosphines such as tris(ortho-tolyl)phosphine. Commercialpalladium complexes such as, for example, the catalysttetrakis(triphenylphosphine)palladium(0) and/or additions of phosphineligands can likewise be employed.

The hydroxy group in the compound IV is then derivatized, for examplewith phenyl chloroformate, to give the compounds Va and/or Vb. Thisconsequently takes place by reaction with reagents such as, for example,carboxylic acids, carbonyl chlorides, carbonic anhydrides,chloroformates, isocyanates or carbamoyl chlorides into the compounds Vof the invention, using generally customary methods (see J. March,Advanced Organic Chemistry, 1992, 4th edition, Wiley, New York, pages417-421; 499; 903). For example, LG can have as leaving group OPh in thecompounds Va and/or Vb which is derived from reaction of IV with phenylchloroformate in the presence of a base such as, for example, pyridine.

Subsequent reaction with excess amines VI, where appropriate at elevatedtemperature and/or with the addition of auxiliary bases such as, forexample, triethylamine or diisopropylethylamine, leads to the compoundsVII. The amines VI can be either purchased or prepared by methods knownfrom the literature.

Compounds such as VII can then be converted by treatment with sulfonylchlorides VIII after deprotonation with a strong base such as, forexample, potassium tert-butoxide or sodium hydride in dimethylformamide(DMF) into the compounds of the invention. The employed sulfonylchlorides VIII can either be purchased or prepared in an analogousmanner to known processes (see, for example, J. Med. Chem. 40, 1149(1997)).

Alternatively, the compounds I of the invention can be preparedaccording to synthesis scheme 2 in the shown three-stage processanalogous to synthesis scheme 1 with alteration of the sequence.

In this case firstly the 3-hydroxyoxindoles IV are sulfonylated bydeprotonation with a strong base such as, for example, sodium hydride orpotassium tert-butoxide and subsequent treatment with sulfonyl chloridesVIII in DMF. In the next step, derivatization of the hydroxy group in IXfollows to give the compound X by treatment for example with phenylchloroformate. Finally, the compounds I of the invention are generatedin an excess of amine VI or else with the assistance of an auxiliarybase.

A further preparation possibility and derivatization by R³ in the amineVI is represented by the reaction of amines with aldehydes or ketones inthe presence of reducing agents such as, for example, sodiumcyanoborohydride or sodium acetoxyborohydride in the manner of areductive amination (J. March, Advanced Organic Chemistry, 1992, 4thedition, Wiley, New York, pages 411; 898).

A further aspect of the present invention relates to a pharmaceuticalcomposition comprising at least one compound of the general formula Iand/or a pharmaceutically acceptable salt or a prodrug thereof asdetailed above, and a pharmaceutically acceptable carrier. Suitablecarriers depend inter alia on the dosage form of the composition and areknown in principle to the skilled worker. Some suitable carriers aredescribed hereinafter.

A further aspect of the present invention relates to the use ofcompounds of the formula I and/or of pharmaceutically acceptable saltsor prodrugs thereof for the manufacture of a medicament for thetreatment and/or prophylaxis of vasopressin-dependent diseases.

Vasopressin-dependent diseases are those in which the progress of thedisease is at least partly dependent on vasopressin, i.e. diseases whichshow an elevated vasopressin level which may contribute directly orindirectly to the pathological condition. In other words,vasopressin-dependent diseases are those which can be influenced bymodulating the vasopressin receptor, for example by administration of avasopressin receptor ligand (agonist, antagonist, partialantagonist/agonist, inverse agonist etc.).

In a preferred embodiment, the present invention relates to the use ofcompounds of the invention of the formula I or of pharmaceuticallyacceptable salts or prodrugs thereof for the manufacture of a medicamentfor the treatment and/or prophylaxis of diseases selected from diabetes,insulin resistance, nocturnal enuresis, incontinence and diseases inwhich impairments of blood clotting occur, and/or for delayingmicturition. The term “diabetes” means all types of diabetes, especiallydiabetes mellitus (including type I and especially type II), diabetesrenalis and in particular diabetes insipidus. The types of diabetes arepreferably diabetes mellitus of type II (with insulin resistance) ordiabetes insipidus.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofdiseases selected from hypertension, pulmonary hypertension, heartfailure, myocardial infarction, coronary spasm, unstable angina, PTCA(percutaneous transluminal coronary angioplasty), ischemias of theheart, impairments of the renal system, edemas, renal vasospasm,necrosis of the renal cortex, hyponatremia, hypokalemia,Schwartz-Bartter syndrome, impairments of the gastrointestinal tract,gastritic vasospasm, hepatocirrhosis, gastric and intestinal ulcers,emesis, emesis occurring during chemotherapy, and travel sickness.

The compounds of the invention of the formula I or theirpharmaceutically acceptable salts or their prodrugs or thepharmaceutical composition of the invention can also be used for thetreatment of various vasopressin-dependent complaints which have centralnervous causes or alterations in the HPA axis (hypothalamic pituitaryadrenal axis), for example for affective disorders such as depressivedisorders and bipolar disorders. These include for example dysthymicdisorders, phobias, post-traumatic stress disorders, general anxietydisorders, panic disorders, seasonal depression and sleep disorders.

The compounds of the invention of the formula I and theirpharmaceutically acceptable salts or their prodrugs or thepharmaceutical composition of the invention can likewise be employed forthe treatment of anxiety disorders and stress-dependent anxietydisorders, such as, for example, generalized anxiety disorders, phobias,post-traumatic anxiety disorders, panic anxiety disorders,obsessive-compulsive anxiety disorders, acute stress-dependent anxietydisorders and social phobia.

The compounds of the invention can furthermore also be employed for thetreatment of memory impairments, Alzheimer's disease, psychoses,psychotic disorders, sleep disorders and/or Cushing's syndrome, and allstress-dependent diseases.

Accordingly, a further preferred embodiment of the present inventionrelates to the use of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of affective disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of anxiety disordersand/or stress-dependent anxiety disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of memory impairmentsand/or Alzheimer's disease.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of psychoses and/orpsychotic disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of Cushing's syndrome orother stress-dependent diseases.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of sleep disorders.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of depressive disorders. Aparticular form of depressive disorders are so-called childhood onsetmood disorders, i.e. depressive moods having their onset in childhood.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment of vasomotor symptomsand/or thermoregulatory dysfunctions such as, for example, the hot flushsymptom.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment and/or prophylaxis of drugor pharmaceutical dependencies and/or dependencies mediated by otherfactors, for the treatment and/or prophylaxis of stress caused bywithdrawal of one or more factors mediating the dependence and/or forthe treatment and/or prophylaxis of stress-induced relapses into drug orpharmaceutical dependencies and/or dependencies mediated by otherfactors.

In a further preferred embodiment, the present invention relates to theuse of compounds of the invention of the formula I or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofschizophrenia and/or psychosis.

A further aspect of the invention relates to a method for the treatmentand/or prophylaxis of vasopressin-dependent diseases, in which aneffective amount of at least one compound of the invention of theformula I or of at least one pharmaceutically acceptable salt or oneprodrug thereof or of a pharmaceutical composition of the invention isadministered to a patient.

Concerning the definition of vasopressin-dependent diseases, referenceis made to the above statements.

In a preferred embodiment of the invention, the method of the inventionserves for the treatment and/or prophylaxis of disorders selected fromdiabetes, insulin resistance, nocturnal enuresis, incontinence anddiseases in which impairments of blood clotting occur, and/or fordelaying micturition. Concerning the definition of diabetes, referenceis made to the above statements.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of disorders selected fromhypertension, pulmonary hypertension, heart failure, myocardialinfarction, coronary spasm, unstable angina, PTCA (percutaneoustransluminal coronary angioplasty), ischemias of the heart, impairmentsof the renal system, edemas, renal vasospasm, necrosis of the renalcortex, hyponatremia, hypokalemia, Schwartz-Bartter syndrome,impairments of the gastrointestinal tract, gastritic vasospasm,hepatocirrhosis, gastric and intestinal ulcers, emesis, emesis occurringduring chemotherapy, and travel sickness.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of affective disorders.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of anxiety disorders and/orstress-dependent anxiety disorders.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of memory impairments and/orAlzheimer's disease.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of psychoses and/or psychoticdisorders.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of Cushing's syndrome.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of sleep disorders in a patient.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of depressive disorders. In thecase of depressive disorders, specific mention is also to be made ofchildhood onset mood disorders, i.e. depressive moods having their onsetin childhood.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of vasomotor symptoms and/orthermoregulatory dysfunctions, such as, for example, the hot flushsymptom.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of drug or pharmaceuticaldependencies and/or dependencies mediated by other factors, for thetreatment and/or prophylaxis of stress caused by withdrawal of one ormore factors mediating the dependence, and/or for the treatment and/orprophylaxis of stress-induced relapses into drug or pharmaceuticaldependencies and/or dependencies mediated by other factors.

In a further preferred embodiment, the method of the invention servesfor the treatment and/or prophylaxis of schizophrenia and/or psychosis.

The patient to be treated prophylactically or therapeutically with themethod of the invention is preferably a mammal, for example a human or anonhuman mammal or a nonhuman transgenic mammal. Specifically it is ahuman.

The compounds of the general formula I, their pharmaceuticallyacceptable salts and prodrugs as detailed above can be prepared by askilled worker with knowledge of the technical teaching of the inventionin implementing and/or in analogous implementation of process stepsknown per se.

The compounds I or their prodrugs and/or their pharmaceuticallyacceptable salts are distinguished by having a selectivity for thevasopressin V1b receptor subtype vis-à-vis at least one of the closelyrelated vasopressin/oxytocin receptor subtypes (for example vasopressinV1a, vasopressin V2 and/or oxytocin).

Alternatively, or preferably in addition, the compounds I or theirprodrugs and/or their pharmaceutically acceptable salts aredistinguished by having an improved metabolic stability.

The metabolic stability of a compound can be measured for example byincubating a solution of this compound with liver microsomes fromparticular species (for example rat, dog or human) and determining thehalf-life of the compound under these conditions (R S Obach, Curr OpinDrug Discov Devel. 2001, 4, 36-44). It is possible in this connection toconclude from an observed longer half-life that the metabolic stabilityof the compound is improved. The stability in the presence of humanliver microsomes is of particular interest because it makes it possibleto predict the metabolic degradation of the compound in the human liver.Compounds with increased metabolic stability (measured in the livermicrosome test) are therefore probably also degraded more slowly in theliver. The slower metabolic degradation in the liver may lead to higherand/or longer-lasting concentrations (active levels) of the compound inthe body, so that the elimination half-life of the compounds of theinvention is increased. Increased and/or longer-lasting active levelsmay lead to a better activity of the compound in the treatment orprophylaxis of various vasopressin-dependent diseases. In addition, animproved metabolic stability may lead to an increased bioavailabilityafter oral administration, because the compound is subject, afterabsorption in the intestine, to less metabolic degradation in the liver(so-called first pass effect). An increased oral bioavailability may,owing to an increased concentration (active level) of the compound, leadto a better activity of the compound after oral administration.

Alternatively, or preferably in addition, the compounds I or theirprodrugs and/or their pharmaceutically acceptable salts aredistinguished by having an improved pharmacological activity, comparedwith the oxindole compounds known from the prior art, in patients orrelevant animal models which enable prognostic statements for use in thetreatment.

The compounds of the invention are effective after administration byvarious routes. Possible examples are intravenous, intramuscular,subcutaneous, topical, intratracheal, intranasal, transdermal, vaginal,rectal, sublingual, buccal or oral administration, and administration isfrequently intravenous, intramuscular or, in particular, oral.

The present invention also relates to pharmaceutical compositions whichcomprise an effective dose of a compound I of the invention, of apharmaceutically acceptable salt or of a prodrug thereof and suitablepharmaceutical carriers (drug carriers).

These drug carriers are chosen according to the pharmaceutical form andthe desired mode of administration and are known in principle to theskilled worker.

The compounds of the invention of the formula I or optionally suitablesalts of these compounds can be used to produce pharmaceuticalcompositions for oral, sublingual, buccal, subcutaneous, intramuscular,intravenous, topical, intratracheal, intranasal, transdermal, vaginal orrectal administration, and be administered to animals or humans inuniform administration forms, mixed with conventional pharmaceuticalcarriers, for the prophylaxis or treatment of the above disorders ordiseases.

The suitable administration forms (dose units) include forms for oraladministration such as tablets, gelatin capsules, powders, granules andsolutions or suspensions for oral intake, forms for sublingual, buccal,intratracheal or intranasal administration, aerosols, implants, forms ofsubcutaneous, intramuscular or intravenous administration and forms ofrectal administration.

The compounds of the invention can be used in creams, ointments orlotions for topical administration.

In order to achieve the desired prophylactic or therapeutic effect, thedose of the active ingredient can vary between 0.01 and 50 mg per kg ofbody weight and per day.

Each unit dose may comprise from 0.05 to 5000 mg, preferably 1 to 1000mg, of the active ingredient in combination with a pharmaceuticalcarrier. This unit dose can be administered once to 5 times a day, sothat a daily dose of from 0.5 to 25 000 mg, preferably 1 to 5000 mg, isadministered.

If a solid composition is prepared in the form of tablets, the activeingredient is mixed with a solid pharmaceutical carrier such as gelatin,starch, lactose, magnesium stearate, talc, silicon dioxide or the like.

The tablets can be coated with sucrose, a cellulose derivative oranother suitable substance or be treated otherwise in order to display asustained or delayed activity and to release a predetermined amount ofthe active ingredient continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with an extender and including the resulting mixturein soft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration inthe form of drops may contain active ingredients together with asweetener, which is preferably calorie-free, methylparaben orpropylparaben as antiseptics, a flavoring and a suitable coloringsubstance.

Water-dispersible powders or granules may comprise the activeingredients mixed with dispersants, wetting agents or suspending agents,such as polyvinylpyrrolidones, and sweeteners or masking flavors.

Rectal or vaginal administration is achieved by using suppositorieswhich are prepared with binders which melt at rectal temperature, forexample cocoa butter or polyethylene glycols. Parenteral administrationis effected by using aqueous suspensions, isotonic saline solutions orsterile and injectable solutions which comprise pharmacologicallyacceptable dispersants and/or wetting agents, for example propyleneglycol or polyethylene glycol.

The active ingredient may also be formulated as microcapsules orcentrosomes, if suitable with one or more carriers or additives.

The compositions of the invention may, in addition to the compounds ofthe invention, comprise other active ingredients which may be beneficialfor the treatment of the disorders or diseases indicated above.

The present invention thus further relates to pharmaceuticalcompositions in which a plurality of active ingredients are presenttogether, where at least one of these is a compound I of the invention,salt or a prodrug thereof.

The invention is explained in more detail below by means of examples,but the examples are not to be understood to be restrictive.

The compounds of the invention can be prepared by various syntheticroutes. The methods mentioned, as described accordingly in synthesisschemes 1 and 2, are explained in greater detail merely by way ofexample using the given examples without being exclusively restricted tosynthesis routes 1 or 2 or analogous methods.

EXPERIMENTAL SECTION Abbreviations

-   THF: tetrahydrofuran-   DMSO: dimethyl sulfoxide-   TFA: trifluoroacetic acid-   p: pseudo (for example pt pseudo triplet)-   b: broad (for example bs broad singlet)-   s: singlet-   d: doublet-   t: triplet-   m: multiplet-   dd: doublet of doublets-   dt: doublet of triplets-   tt: triplet of triplets

I. Preparation of the Starting Compound VI a)1-Ethyl-4-piperidin-4-yl-piperazine a.1) tert-Butyl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate

29.2 g (256 mmol) of N-ethylpiperazine were introduced with 50.0 g (256mmol) of tert-butyl 4-oxopiperidine-1-carboxylate (corresponds to1-Boc-4-piperidone) into 800 ml of ethanol while cooling in ice. 15.4 g(256 mmol) of glacial acetic acid were added. Then 16.1 g (256 mmol) ofsodium acetoxyborohydride were added in portions to the cooled reactionmixture. Initially slight gas formation was observed and, after additionof ⅔ of the reducing agent, foam formation was observed. The reactionmixture was stirred at room temperature overnight. The reaction solutionwas worked up by adding 200 ml of 2N of sodium hydroxide solution whilecooling, distilling out the solvent ethanol and diluting the remainingreaction mixture with water. It was extracted with diethyl ether (2×)and was washed with saturated sodium chloride solution (1×), and thecombined organic phases were dried over magnesium sulfate and filtered,and the solvent was removed in vacuo. The crude title compound wasobtained as a yellow oil which was then chromatographed on a 4 l suctionfunnel filled with silica gel using dichloromethane and 10% methanol aseluent. In total, 40 g (135 mmol, 53%) of tert-butyl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate were obtained.

a.2) 1-Ethyl-4-piperidin-4-ylpiperazine as chloride salt

The protective group was removed by introducing 40 g (135 mmol) oftert-butyl 4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate fromexample a.1 into 200 ml of methanol and 1.8 l of dichloromethane andadding 100 ml of 5-6M HCl solution in isopropanol. A suspensionresulted, and slight gas evolution was also observable. The reactionmixture was stirred at 40° C. (water bath temperature) for one hour andthen stirred at room temperature for 48 hours. For completedeprotection, 50 ml of the 5-6M HCl solution in isopropanol were againadded and the reaction mixture was stirred at 40° C. The dichloromethanewas distilled out in a rotary evaporator. 200 ml of methanol and 30 mlof the 5-6M HCl solution in isopropanol were again added. The reactionmixture was stirred under reflux for one hour, during which a whitesuspension formed with strong evolution of gas. A mobile suspension thenresulted and was cooled to room temperature. The precipitate wasfiltered off with suction and washed with methanol and diethyl ether.After drying, 36 g (117 mmol, 87%) of 1-ethyl-4-piperidin-4-ylpiperazinewere isolated as chloride salt.

¹H-NMR (D₂O, 400 MHz) δ[ppm]=3.74-3.47 (m, 11H), 3.28 (q, 2H, J=7.3 Hz),3.06 (dt, 2H, J=2.2 Hz, J=13.2 Hz), 2.38 (m, 2H, J=13.6 Hz), 1.89 (dq,2H, J=4.1 Hz, J=13.3 Hz), 1.30 (t, 3H, J=7.3 Hz).

II. Preparation of the Racemic Compounds of the Formula I Example 1(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 1.1(±)-3-(2-Ethoxypyridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydro-2H-indol-2-one

3.22 g (80.50 mmol, 60% w/w) of sodium hydride were added in portions to20.86 g (76.40 mmol) of 5-iodoisatin in 400 ml of anhydroustetrahydrofuran (THF) while stirring and cooling in an ice bath, keepingthe temperature at between 0-10° C. The resulting suspension was stirredwhile cooling in an ice bath for one hour. To prepare the pyridineGrignard 20 g (80.30 mmol) of 2-ethoxy-3-iodopyridine were dissolved in400 ml of anhydrous THF at room temperature. 95.6 ml (1 M solution inTHF, 95.60 mmol) of ethylmagnesium bromide were added to this solutionwhile cooling at a temperature between 22 and 15° C. over a period of5-10 minutes. The solution was stirred for 20 minutes, during which itbecame a pale yellowish color from colorless.

The solution of the pyridine Grignard was then added to the solution,cooled in an ice bath, of the 5-iodoisatin sodium salt at a temperaturebetween 5 and 18° C. over a period of 5-10 minutes. After addition ofthe pyridine Grignard was complete, the ice bath was removed. Thereaction mixture was stirred at room temperature for 2 hours. An excessof saturated ammonium chloride solution was added, followed by ethylacetate, the mixture being stirred for 5 minutes. The aqueous phase wasseparated off and extracted with ethyl acetate (2×). The combinedorganic phases were washed with water (2×), and the solvent was removedin vacuo. During this, unreacted 5-iodoisatin precipitated first fromthe still dilute solution and was separated off. After furtherconcentration, finally the title compound also crystallized. Thesuspension was stored in a refrigerator at 5° C. for 2 hours. Theprecipitated, pale yellow solid was then filtered off and washed with alittle ethyl acetate. After drying at 40° C.,(±)-3-(2-ethoxypyridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydro-2H-indol-2-one(17.1 g, 43.16 mmol, 57%) was isolated.

ESI-MS [M+H⁺]=397.05 calculated for C₁₅H₁₃IN₂O₃=396.19.

1.2(±)-5-Cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one

7.1 g (17.92 mmol) of(±)-3-(2-ethoxypyridin-3-yl)-3-hydroxy-5-iodo-1,3-dihydro-2H-indol-2-onefrom example 1.1 were stirred in 100 ml of anhydrous THF under anitrogen atmosphere at room temperature. 2.1 g (17.92 mmol) of zinccyanide were added, followed by 0.51 g (0.45 mmol) of the catalysttetrakis(triphenylphosphine)palladium(0). The reaction mixture wasimmediately placed in a preheated oil bath at a temperature of 100° C.The mixture was stirred at 100° C. (oil-bath temperature) and, after 30minutes, a further 0.51 g (0.45 mmol) of the catalyst was added. Themixture was stirred for a total of 2 hours. The reaction mixture wasallowed to cool to room temperature and an excess of water was added. Itwas subsequently extracted with ethyl acetate (3×), and the combinedorganic phases were washed with water (3×). The solvent was evaporatedto dryness in vacuo, and the residue was slurried with a small volume ofethyl acetate. A pale yellow solid could be filtered off and was washedwith ethyl acetate and dried in a vacuum drying oven. 3.7 g (12.44 mmol,69.4%) of5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one wereobtained.

ESI-MS [M+H⁺]=296.05 calculated for C₁₆H₁₃N₃O₃=295.30.

1.3 (±)-Phenyl5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-3-[(phenoxycarbonyl)oxy]indoline-1-carboxylate

4.63 ml (36.98 mmol) of phenyl chloroformate were slowly added dropwise,undiluted, at the preset temperature to a suspension, cooled to 0° C.,of 5.20 g (17.61 mmol) of(±)-5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-onefrom example 1.2 in 100 ml of pyridine. After the reaction mixture hadthawed to room temperature it was stirred for 2 hours. The progress ofthe reaction was followed by thin-layer chromatography (silica gel,dichloromethane/methanol 9:1). Excess pyridine was removed in vacuo, andthe residue was poured into 200 ml of ice-water and extracted with ethylacetate (3×). The organic phase was washed with water (2×). Traces ofpyridine were still present in the phase. The organic phase was driedover sodium sulfate. After removal of the ethyl acetate in vacuo, theremaining pyridine was driven off by addition of toluene and removal invacuo several times. The residue was dried under high vacuum. 8.20 g(15.31 mmol, 87%) of phenyl5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-3-[(phenoxycarbonyl)-oxy]indoline-1-carboxylatewere obtained.

ESI-MS [M+H⁺]=536.25 calculated for C₃₀H₂₁N₃O₇=535.52.

1.4 (±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

2.74 g (14.94 mmol) of 1-(1-methylpiperidin-4-yl)piperazine were addedto a solution of 1.60 g (2.89 mmol) of (±)-phenyl5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-3-[(phenoxycarbonyl)oxy]indoline-1-carboxylatefrom example 1.3 in 50 ml of THF. During this, initially a slightturbidity formed and eventually a precipitate separated out. Afterstirring at room temperature for 2 hours, the reaction was complete(checked by thin-layer chromatography (silica gel,dichloromethane/methanol 9:1)). The mixture was stirred overnight. Theprecipitate was filtered off with suction and washed with THF anddiethyl ether. 0.923 g (1.829 mmol, 61%) of5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate was obtained. Thetitle compound was pure according to MS and HPLC. The mother liquorcontained only traces of the title compound plus the byproduct phenyl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate.

ESI-MS [M+H⁺]=505.25 calculated for C₂₇H₃₂N₆O₄=504.59.

1.5(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

24.47 mg (0.22 mmol) of potassium tert-butoxide were added undiluted toa solution of 100 mg (0.20 mmol) of(±)-5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate in 2 ml of absolutedimethylformamide while cooling at 0° C. The reaction mixture wasstirred at 0° C. for one hour. A clear colorless solution formed. At 0°C., 51.6 mg (0.22 mmol) of 2,4-dimethoxybenzenesulfonyl chloride wereadded. The reaction mixture was allowed to thaw to room temperature andwas stirred at room temperature overnight. After conversion wascomplete, the reaction mixture was poured into 10 ml of ice-water andinitially neutralized and then adjusted to pH 9 with 2 ml of 1 N sodiumhydroxide solution. A precipitate separated out and was washed withwater and dried in a vacuum drying oven to result in 68 mg of dry solid.In order to remove the slight impurities, the solid was stirred in 3 mlof diethyl ether. After leaving to stand overnight, the solid was againfiltered off and washed with a little diethyl ether and dried. 40 mg(0.06 mmol, 29%) of(±)-5-cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate were obtained.

ESI-MS [M+H⁺]=705.4 calculated for C₃₅H₄₀N₆O₈S=704.81.

¹H-NMR ([d₆]-DMSO, 500 MHz) δ [ppm]=8.22-8.10 (m, 2H), 7.96 (d, 1H,J=8.0 Hz), 7.92 (d, 1H, J=8.3 Hz), 7.85 (d, 1H, J=8.7 Hz), 7.65 (s, 1H),7.13 (m, 1H), 6.67-6.63 (m, 2H), 4.08 (m, 2H), 3.84 (s, 3H), 3.67-3.45(m, 3H), 3.51 (s, 3H), 3.04 (m, 2H), 2.74 (pd, 2H, J=9.4 Hz), 2.46 (m,1H), 2.28 (m, 2H), 2.14 (m, 1H), 2.10 (s, 3H), 1.79 (pt, 2H, J=10.3 Hz),1.61 (pd, 2H, J=10.2 Hz), 1.36 (m, 2H), 0.99 (t, 3H, J=6.4 Hz).

The compounds I of the invention can also be purified as an alternativeto crystallization by conventional normal-phase column chromatography(such as, for example, NP SiO₂ cartridge, Chromabond anddichloromethane/methanol as eluent) and/or by preparative HPLC (RP,eluent acetonitrile/water, 0.1% TFA or 0.1% acetic acid). Compounds Ithen result where appropriate as trifluoroacetic acid salt,bis(trifluoroacetic acid) salt or acetic acid salt.

Examples 2 to 90

The compounds of the formula I according to examples 2 to 90 can beprepared using the appropriate starting compounds in analogy to theprocess for preparing example 1.

Example 2(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS [M+H⁺]=675.15 calculated for C₃₄H₃₈N₆O₇S=674.78.

Example 4(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS [M+H⁺]=645.20 calculated for C₃₃H₃₆N₆O₆S=644.76.

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.18-8.15 (m, 2H), 8.05 (d, 2H, J=7.5Hz), 7.97 (d, 1H, J=8.6 Hz), 7.93 (dd, 1H, J=1.7 Hz, J=8.6 Hz), 7.79(pt, 1H, J=7.5 Hz), 7.70 (pd, 1H, J=1.6 Hz), 7.66 (pt, 2H, J=7.9 Hz),7.15 (dd, 1H, J=5.1 Hz, J=7.5 Hz), 4.05 (m, 1H), 3.88 (m, 1H), 3.55 (m,2H), 3.03 (m, 2H), 2.97 (m, 2H), 2.47-2.21 (m, 10H), 1.74 (m, 2H), 1.51(m, 2H), 0.89 (t, 3H, J=7.1 Hz).

Example 5(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS [M+H⁺]=675.15 calculated for C₃₄H₃₈N₆O₇S=674.78.

Example 10(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate, trifluoroacetic acidsalt

4 μl (0.06 mmol) of acetaldehyde were added dropwise to 50 mg (0.06mmol) of5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-piperidin-4-ylpiperazine-1-carboxylate in the form of thebis(trifluoroacetic acid) salt from example 28 in 5 ml ofdimethylformamide. The mixture was stirred for 5 minutes. To thissuspension were added firstly 41.3 mg (0.29 mmol) of sodium sulfate andthen 10 μl (0.12 mmol) of glacial acetic acid, and the mixture wasstirred for one hour. 18.5 mg (0.09 mmol) of sodium acetoxyborohydridewere introduced in one portion, whereupon an almost clear solutionformed within 15 minutes. The progress of the reaction was followed byLC-MS (RP, acetonitrile/water as eluent and 0.1% TFA). After conversionwas complete, the mixture was diluted with water and adjusted to pH 10with 2N sodium hydroxide solution. After removal of the organic phase,the aqueous phase was extracted again with dichloromethane (2×), thecombined organic phase was dried over magnesium sulfate and filtered,and the solvent was removed in vacuo. 35 mg of the crude title compoundwere isolated and were purified by preparative HPLC on a chromolithcolumn (normal phase, from Merck) with the eluents dichloromethane andmethanol (gradient 0-5% by volume of methanol within 15 min). Sincebyproduct (the desulfonylated analog of the product) was detectable inaddition to the title compound, it was purified again by preparativeHPLC (RP, eluent acetonitrile/water, 0.1% TFA). 19 mg (0.027 mmol, 45%)of5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-(1-ethylpiperidin-4-yl)piperazine-1-carboxylate, trifluoroacetic acidsalt were isolated.

ESI-MS [M+H⁺]=659.3 calculated for C₃₄H₃₈N₆O₆S=658.78.

Example 25(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-piperidin-4-ylpiperazine-1-carboxylate as bis(trifluoroacetic acid)salt

0.159 mg (1.391 mmol) of trifluoroacetic acid was added dropwise to asolution of 0.220 g (0.278 mmol) of5-cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl-4-[1-(tert-butoxycarbonyl)piperidine-4-yl]piperazine-1-carboxylate(prepared in analogy to example 1, process stage 1.1) to 1.5)) in 3 mlof dichloromethane. The reaction mixture was stirred at room temperaturefor one hour, monitoring the reaction by thin-layer chromatography(dichloromethane/methanol 9:1). The solvent was removed in vacuo, andthe residue (304 mg) was then purified by preparative HPLC (RP, eluentacetonitrile/water, 0.1% TFA), with 20 mg (0.022 mol, 8%) of5-cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-piperidin-4-ylpiperazine-1-carboxylate as bis(trifluoroacetic acid)salt being isolated.

ESI-MS [M+H⁺]=691.25 calculated for C₃₄H₃₈N₆O₈S=690.78.

Example 28(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-piperidin-4-ylpiperazine-1-carboxylate as bis(trifluoroacetic acid)salt

ESI-MS [M+H⁺]=631.20 calculated for C₃₂H₃₄N₆O₆S=630.73.

Example 31(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate

ESI-MS [M+H⁺]=705.25 calculated for C₃₅H₄₀N₆O₈S=704.81.

Example 32(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate

ESI-MS [M+H⁺]=675.15 calculated for C₃₄H₃₈N₆O₇S=674.78.

Example 34(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate

ESI-MS [M+H⁺]=645.15 calculated for C₃₃H₃₆N₆O₆S=644.76.

Example 35(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(4-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-methylpiperazin-1-yl)piperidine-1-carboxylate

ESI-MS [M+H⁺]=675.25 calculated for C₃₄H₃₈N₆O₇S=674.78.

Example 37(±)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate

ESI-MS [M+H⁺]=719.30 calculated for C₃₆H₄₂N₆O₈S=718.84.

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.19 (dd, 1H, J=1.6 Hz, J=4.9 Hz,8.15 (dd, 1H, J=1.6 Hz, J=7.6 Hz), 7.97 (m, 2H), 7.87 (d, 1H, J=8.7 Hz),7.69 (m, 1H), 7.16 (dd, 1H, J=5.0 Hz, J=7.6 Hz), 6.72-6.68 (m, 2H), 4.19(m, 1H), 4.10 (m, 2H), 3.86 (s, 3H), 3.74 (m, 2H), 3.52 (s, 3H),3.58-3.50 (m, 2H), 3.08-2.44 (m, 11H), 1.57 (m, 3H), 1.18 (m, 3H), 1.01(t, 3H, J=6.8 Hz).

Example 40(±)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate

ESI-MS [M+H⁺]=659.30 calculated for C₃₄H₃₈N₆O₆S=658.78.

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.19-8.17 (m, 2H), 8.07 (d, 2H, J=7.7Hz), 7.99 (d, 1H, J=8.6 Hz), 7.95 (m, 1H, J=8.4 Hz), 7.81 (t, 1H, J=7.5Hz), 7.73 (d, 1H, J=32.5 Hz), 7.67 (pt, 2H, J=7.8 Hz), 7.17 (dd, 1H,J=5.0 Hz, J=7.6 Hz), 4.18-4.04 (m, 2H), 3.92 (m, 1H), 3.43 (m, 2H), 3.01(m, 1H), 2.62 (m, 1H), 2.45-2.25 (m, 11H), 1.79 (m, 1H), 1.61 (m, 1H),1.36 (m, 1H), 1.09 (m, 1H), 0.97 (m, 3H), 0.92 (t, 3H, J=7.1 Hz).

Example 555-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-piperazin-1-ylpiperidine-1-carboxylate as bis(trifluoroacetic acid)salt

ESI-MS [M+H⁺]=691.25 calculated for C₃₄H₃₈N₆O₈S=690.78.

III. Preparation of Chiral Compounds of the General Formula I A.)Racemate Resolution of Compounds of the Formula I

Racemic compounds of the formula I can be resolved for example byseparation on a preparative chiral column.

Example 1A and Example 1B(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate (example 1A) and(−)-5-cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate (example 1B)

68 mg (0.096 mmol) of the racemic5-cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate from example 1 wereresolved on a preparative chiral column (Chiracel OD, flow rate 55ml/min) with n-heptane/ethanol (700:300) as eluent. The enantiomereluted first (example 1A) with positive rotation (rotation determined inchloroform) could be isolated in a yield of 20 mg (0.028 mmol, 29%), andthe subsequent enantiomer (example 1B) with negative rotation (rotationdetermined in chloroform) could be isolated in a yield of 17 mg (0.024mmol, 25%).

Example 1A(+)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS [M+H⁺]=353.4 (½ mass) calculated for C₃₅H₄₀N₆O₈S=704.81.

HPLC (Chiracel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=9.10 min.

Rotation α (22° C., 589 nm, CHCl₃, 1 mg/ml)=plus rotation

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.16 (dd, 1H, J=1.7 Hz, J=4.9 Hz),8.12 (dd, 1H, J=1.7 Hz, J=7.6 Hz), 7.97-7.91 (m, 2H), 7.85 (pd, 1H,J=8.8 Hz), 7.66 (d, 1H, J=36.9 Hz), 7.13 (dd, 1H, J=5.0 Hz, J=7.6 Hz),6.66 (m, 2H), 4.15 (m, 1H), 4.09 (q, 2H, J=6.9 Hz), 3.84 (s, 3H),3.53-3.48 (m, 1H), 3.50 (s, 3H), 2.97 (pt, 1H, J=12.1 Hz), 2.62 (pt, 1H,J=12.6 Hz), 2.40-2.25 (m, 9H), 2.11 (s, 3H), 1.74 (m, 1H), 1.58 (m, 1H),1.37-1.26 (m, 1H), 1.04 (m, 1H), 1.00 (t, 3H, J=7.1 Hz).

Example 1B(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS [M+H⁺]=353.45 (½ mass) calculated for C₃₅H₄₀N₆O₈S=704.81.

HPLC (Chiracel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=15.91 min.

Rotation α (22° C., 589 nm, CHCl₃, 1 mg/ml)=minus rotation

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.17 (dd, 1H, J=1.7 Hz, J=4.9 Hz),8.12 (dd, 1H, J=1.7 Hz, J=7.6 Hz), 7.97-7.91 (m, 2H), 7.84 (pd, 1H,J=8.5 Hz), 7.66 (d, 1H, J=37.5 Hz), 7.14 (dd, 1H, J=5.0 Hz, J=7.6 Hz),6.66 (m, 2H), 4.15 (m, 1H), 4.08 (q, 2H, J=6.9 Hz), 3.84 (s, 3H), 3.51(s+m, 4H), 2.98 (pt, 1H, J=12.0 Hz), 2.62 (pt, 1H, J=11.1 Hz), 2.47-2.21(m, 9H), 2.12 (s, 3H), 1.74 (m, 1H), 1.57 (m, 1H), 1.40-1.23 (m, 1H),1.04 (m, 1H), 1.00 (t, 3H, J=7.1 Hz).

The racemates of examples 2 to 90 can be resolved in an analogous mannerto result in the corresponding (+) enantiomers 2A, 3A, 4A, 5A, 6A, 7A,8A, 9A, 10A, 11A, 12A, 13A, 14A, 15A, 16A, 17A, 18A, 19A, 20A, 21A, 22A,23A, 24A, 25A, 26A, 27A, 28A, 29A, 30A, 31A, 32A, 33A, 34A, 35A, 36A,37A, 38A, 39A, 40A, 41A, 42A, 43A, 44A, 45A, 46A, 47A, 48A, 49A, 50A,51A, 52A, 53A, 54A, 55A, 56A, 57A, 58A, 59A, 60A, 61A, 62A, 63A, 64A,65A, 66A, 67A, 68A, 69A, 70A, 71A, 72A, 73A, 74A, 75A, 76A, 77A, 78A,79A, 80A, 81A, 82A, 83A, 84A, 85A, 86A, 87A, 88A, 89A and 90A

and the corresponding (−) enantiomers 2B, 3B, 4B, 5B, 6B, 7B, 8B, 9B,10B, 11B, 12B, 13B, 14B, 15B, 16B, 17B, 18B, 19B, 20B, 21B, 22B, 23B,24B, 25B, 26B, 27B, 28B, 29B, 30B, 31B, 32B, 33B, 34B, 35B, 36B, 37B,38B, 39B, 40B, 41B, 42B, 43B, 44B, 45B, 46B, 47B, 48B, 49B, 50B, 51B,52B, 53B, 54B, 55B, 56B, 57B, 58B, 59B, 60B, 61B, 62B, 63B, 64B, 65B,66B, 67B, 68B, 69B, 70B, 71B, 72B, 73B, 74B, 75B, 76B, 77B, 78B, 79B,80B, 81B, 82B, 83B, 84B, 85B, 86B, 87B, 88B, 89B and 90B.

Example 2A(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS [M+H⁺]=675.20 calculated for C₃₄H₃₈N₆O₇S=674.78.

HPLC (Chiracel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=10.10 min.

Rotation α (22° C., 589 nm, CHCl₃, 1 mg/ml)=plus rotation

Example 2B(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-1-[(2-methoxyphenyl)sulfonyl]-2-oxo-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

ESI-MS [M+H⁺]=675.20 calculated for C₃₄H₃₈N₆O₇S=674.78.

HPLC (Chiracel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R₁=12.73 min.(ee=80%)

Rotation α (22° C., 589 nm, CHCl₃, 1 mg/ml)=minus rotation

B.) Synthesis of the (+) and (−) Enantiomers of the Compound of theFormula I Using Enantiopure Precursors and Intermediates

The (+) enantiomer of the formula I and the (−) enantiomer of theformula I can also be prepared using enantiopure precursors andintermediates for example in analogy to synthesis scheme 1 or 2,preferably in accordance with synthesis scheme 2. The enantiomerseparation is to be explained in detail in relation to intermediate IV,racemic5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one,without being restricted thereto. Resolution of the racemate into theenantiomers can take place by preparative chiral chromatography.

Resolution of racemic5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one:

After chromatographic separation of 10.0 g (33.86 mmol) of the racemic5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one fromexample 1.2, 4.85 g (16.42 mmol) of5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-oneeluting first (minus rotation, rotation determined in chloroform) wereisolated with an enantiomeric excess (e.e.) of >99% and 4.66 g (15.78mmol) of5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-oneeluting last (plus rotation, rotation determined in chloroform) wereisolated with an enantiomeric excess (e.e.) of 99%. The enantiomerseparation conditions were a preparative chiral column (Chiralpak AD 20micron 5 cm ID×500 cm) with the eluents hexane/ethanol/methanol in theratio 80/10/10 and a flow rate of 80 ml/min.

Enantiomer 1 of5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one:

ESI-MS [M+H⁺]=296.15 calculated for C₁₆H₁₃N₃O₃=295.30.

HPLC (Chiralpak AD 4.6 mmID×25 cm; hexane/ethanol/methanol 80/10/10)R_(f)=4.61 min.

Rotation α (22° C., 589 nm, CHCl₃, 1 mg/ml)=minus rotation

Enantiomer 2 of5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one:

ESI-MS [M+H⁺]=296.15 calculated for C₁₆H₁₃N₃O₃=295.30.

HPLC (Chiralpak AD 4.6 mmID×25 cm; hexane/ethanol/methanol 80/10/10)R_(f)=6.43 min.

Rotation α (22° C., 589 nm, CHCl₃, 1 mg/ml)=plus rotation

Example 4B illustrates by way of example the synthesis route in analogyto synthesis scheme 2.

Example 4B(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate 4B.1)3-(2-Ethoxypyridin-3-yl)-3-hydroxy-2-oxo-1-(phenylsulfonyl)indoline-5-carbonitrile

2.50 g (7.79 mmol) of(−)-5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one(prepared as in example 1.2 and racemate resolution into thecorresponding enantiomers as described above) were dissolved in 30 ml ofdimethylformamide, resulting in a yellow solution. After cooling to 0°C., 1.00 g (8.94 mmol) of potassium tert-butoxide was added in portionsso that the temperature was kept between 0° C. and 5° C. The solutionchanged in color from yellow to dark yellow. It was stirred for 30minutes and, at 0° C., 1.07 ml (8.20 mmol) of benzenesulfonyl chloridewere slowly added dropwise. The solution became turbid and pale orangein color. It was stirred while cooling in ice for one hour. The progressof the reaction was followed by thin-layer chromatography(dichloromethane/methanol 9:1). For working up, the reaction mixture wasadded dropwise to ice-water. During this, a precipitate separated outand was, after stirring for 5 minutes, filtered off and washed withwater. The title compound (2.65 g, 6.09 mmol, 78%) was dried in a vacuumdrying oven at 40° C. and used for the next reaction without furtherpurification.

ESI-MS [M+H⁺]=436.05 calculated for C₂₂H₁₇N₃O₅S=435.46.

4B.2)5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-ylphenyl carbonate

2.65 g (6.09 mmol) of optically active3-(2-ethoxypyridin-3-yl)-3-hydroxy-2-oxo-1-(phenylsulfonyl)indoline-5-carbonitrilefrom example 4B.1 were dissolved in 4.9 ml of pyridine and 6.0 ml ofdichloromethane while cooling at 0° C. in ice, the solution becomingbrown in color. At this temperature, 1.24 g (7.91 mmol) of phenylchloroformate were slowly added dropwise. The reaction mixture wasstirred in an ice bath for 2 hours. After conversion was complete, thereaction mixture was further diluted with dichloromethane and pouredinto ice-water. The phases were separated, and the organic phase waswashed again with saturated sodium chloride solution (1×) and water(1×). The solvent was evaporated in vacuo, and excess pyridine wasremoved by codistillation with toluene. 50 ml of diisopropyl ether wereadded to precipitate the product, and, after the solid had been filteredoff with suction and washed with diisopropyl ether, a total of 2.16 g(3.89 mmol, 64%) of the optically active5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-ylphenyl carbonate was isolated. Further purification of the mother liquorby normal-phase chromatography with dichloromethane as mobile phaseresulted in 800 mg of the optically active5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-ylphenylcarbonate.

ESI-MS [M+H⁺]=556.15 calculated for C₂₉H₂₁N₃O₇S=555.57.

4B.3)(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate

1.29 g (7.02 mmol) of 1-(1-methylpiperidin-4-yl)piperazine were added toa solution of 1.30 g (2.34 mmol) of optically active5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-ylphenyl carbonate from example 4B.2 in 10 ml of dry tetrahydrofuran(dried over molecular sieves). The reaction mixture was initiallystirred at room temperature for one hour, then again heated to 40° C.until complete conversion was achieved in the reaction. The solvent wasremoved in vacuo, and the residue was again dissolved in 100 ml ofdichloromethane and extracted with water (4×). Saturated sodium chloridesolution was added dropwise to improve phase separation. The combinedorganic phase was dried over magnesium sulfate and filtered, and thesolvent was removed in vacuo. 1.5 g of a yellow-brown foam were obtainedand were again mixed with 1 ml of dichloromethane and 30 ml of diethylether. Stirring resulted in a solid precipitate which was filtered offwith suction. The crystals were purified by column chromatography on apreparative MPLC (ISCO Companion, 12 g NP cartridge) withdichloromethane/methanol as eluent. In total, 0.547 g (0.848 mmol, 36%)of(−)-5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate was obtained. Themother liquor likewise contained product which was also purified bycrystallization and chromatography.

In order to obtain the product also as mesylate salt, 18.41 mg (0.19mmol) of methanesulfonic acid were added to a solution of 130 mg (0.20mmol) of(−)-5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate in 5 ml ofdichloromethane. The reaction mixture was stirred for one hour. Thesolvent was evaporated in vacuo and the residue was dried over anitrogen atmosphere. Last traces of solvent were removed by drying in avacuum drying oven at 35° C. In total, 142 mg (0.19 mmol) of theoptically active5-cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate mesylate wereobtained.

ESI-MS [M+H⁺]=645.25 calculated for C₃₃H₃₆N₆O₆S=644.76.

Rotation α (22° C., 589 nm, CHCl₃, 1 mg/ml)=minus rotation

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.18 (m, 2H), 8.07 (d, 2H, J=7.5 Hz),7.99 (d, 1H, J=8.6 Hz), 7.94 (dd, 1H, J=1.7 Hz, J=8.6 Hz), 7.79 (t, 1H,J=7.5 Hz), 7.71 (d, 1H, J=1.5 Hz), 7.66 (t, 2H, J=7.9 Hz), 7.15 (dd, 1H,J=5.6 Hz, J=7.0 Hz), 4.06 (m, 1H), 3.91 (m, 1H), 3.57 (m, 2H), 2.98 (m,2H), 2.78 (pd, 2H, J=11.3 Hz), 2.47 (m, 2H), 2.29 (m, 2H), 2.18-2.11 (m,1H), 2.14 (s, 3H), 1.85 (pt, 2H, J=11.3 Hz), 1.64 (pd, 2H, J=11.7 Hz),1.39 (m, 2H), 0.92 (t, 3H, J=7.1 Hz).

The compounds of examples 37B and 40B can be prepared using theappropriate starting compounds in analogy to the process for preparingexample 4B.

Example 37B(−)-5-Cyano-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate

ESI-MS [M+H⁺]=719.25 calculated for C₃₆H₄₂N₆O₈S=718.84.

HPLC (Chiracel OD 0.46 cm×25 cm; n-heptane/ethanol 7:3) R_(f)=11.65 min.(ee=80%)

Example 40B(−)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate

ESI-MS [M+H⁺]=659.25 calculated for C₃₄H₃₈N₆O₆S=658.78.

¹H-NMR ([d₆]-DMSO, 500 MHz) δ[ppm]=8.24-8.19 (m, 2H), 8.10 (d, 2H, J=7.7Hz), 8.03 (d, 1H, J=8.6 Hz), 7.97 (m, 1H, J=8.5 Hz), 7.83 (t, 1H, J=7.5Hz), 7.75 (d, 1H, J=31.6 Hz), 7.70 (pt, 2H, J=7.9 Hz), 7.20 (dd, 1H,J=5.1 Hz, J=7.5 Hz), 4.21-4.08 (m, 2H), 3.97 (m, 1H), 3.44 (m, 2H), 3.05(m, 1H), 2.64 (m, 1H), 2.48-2.28 (m, 11H), 1.83 (m, 1H), 1.65 (m, 1H),1.41 (m, 1H), 1.13 (m, 1H), 1.01 (m, 3H), 0.97 (t, 3H, J=7.1 Hz).

(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate, example 4A, can beobtained in analogy to example 4B starting from enantiopure(+)-5-cyano-3-hydroxy-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one(enantiomer with plus rotation [rotation determined in chloroform]) andaccording to process stages 4B.1) to 4B.3) as enantiomer 4A.

Example 4A(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-(1-methylpiperidin-4-yl)piperazine-1-carboxylate as trifluoroaceticacid salt

ESI-MS [M+H⁺]=645.25 calculated for C₃₃H₃₆N₆O₆S=644.76.

The compound of example 40A can be prepared using the appropriatestarting compounds in analogy to the process for preparing example 4A.

Example 40A(+)-5-Cyano-3-(2-ethoxypyridin-3-yl)-2-oxo-1-(phenylsulfonyl)-2,3-dihydro-1H-indol-3-yl4-(4-ethylpiperazin-1-yl)piperidine-1-carboxylate as trifluoroaceticacid salt

ESI-MS [M+H⁺]=659.25 calculated for C₃₄H₃₈N₆O₆S=658.78.

IV. Determination of the Biological Activity 1. Vasopressin V1b ReceptorBinding Assay: Substances:

The test substances were dissolved in a concentration of 10⁻² M in DMSOand further diluted to 5×10⁻⁴ M to 5×10⁻⁹ M. These serial DMSOpredilutions were diluted 1:10 with assay buffer. The substanceconcentration was further diluted 1:5 in the assay mixture (2% DMSO inthe mixture).

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1b receptor (clone3H2) were harvested and homogenized in 50 mM Tris-HCl and in thepresence of protease inhibitors (Roche complete Mini #1836170) using aPolytron homogenizer at intermediate setting for 2×10 seconds, andsubsequently centrifuged at 40 000×g for 1 h. The membrane pellet wasagain homogenized and centrifuged as described and subsequently taken upin 50 mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen inliquid nitrogen at −190° C.

Binding Assay:

The binding assay was carried out by the method based on that of Taharaet al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (250 μl), membranes (50 μg/ml protein in incubationbuffer) from CHO-K1 cells with stably expressed human V1b receptors(cell line hV1b_3H2_CHO) were incubated with 1.5 nM ³H-AVP(8-Arg-vasopressin, PerkinElmer #18479) in incubation buffer (50 mMTris, 10 mM MgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionallywith increasing concentrations of test substance (displacementexperiment). The nonspecific binding was determined with 1 μM AVP(Bachem # H1780). All determinations were carried out as triplicatedeterminations. After incubation (60 minutes at room temperature), thefree radioligand was filtered off by vacuum filtration (Skatron cellharvester 7000) through Wathman GF/B glass fiber filter mats, and thefilters were transferred into scintillation vials. The liquidscintillation measurement took place in a model 2000 or 2200CA Tricarbinstrument (Packard). Conversion of the measured cpm into dpm wascarried out with the aid of a standard quench series.

Analysis:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ³H-AVP for the recombinant human V1b receptors is 0.4nM and was used to determine the Ki.

2. Vasopressin Via Receptor Binding Assay: Substances:

The test substances were dissolved in a concentration of 10⁻² M in DMSO.Further dilution of these DMSO solutions took place in incubation buffer(50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4).

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V1a receptor (clone5) were harvested and homogenized in 50 mM Tris-HCl and in the presenceof protease inhibitors (Roche complete Mini #1836170) using a Polytronhomogenizer at intermediate setting for 2×10 seconds, and subsequentlycentrifuged at 40 000×g for 1 h. The membrane pellet was againhomogenized and centrifuged as described and subsequently taken up in 50mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquidnitrogen at −190° C.

Binding Assay:

The binding assay was carried out by the method based on that of Taharaet al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (250 μl), membranes (20 μg/ml protein in incubationbuffer) from CHO-K1 cells with stably expressed human V1a receptors(cell line hV1a_5_CHO) were incubated with 0.04 nM ¹²⁵I-AVP(8-Arg-vasopressin, NEX 128) in incubation buffer (50 mM Tris, 10 mMMgCl₂, 0.1% BSA, pH 7.4) (total binding) or additionally with increasingconcentrations of test substance (displacement experiment). Thenonspecific binding was determined with 1 μM AVP (Bachem # H1780).Triplicate determinations were carried out.

After incubation (60 minutes at room temperature), the free radioligandwas filtered off by vacuum filtration (Skatron cell harvester 7000)through Wathman GF/B glass fiber filter mats, and the filters weretransferred into scintillation vials.

The liquid scintillation measurement took place in a model 2000 or2200CA Tricarb instrument (Packard). Conversion of the measured cpm intodpm was carried out with the aid of a standard quench series.

Analysis:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ¹²⁵I-AVP for the recombinant hV1a receptors wasdetermined in saturation experiments. A Kd of 1.33 nM was used todetermine the Ki.

3. Vasopressin V2 Receptor Binding Assay: Substances:

The test substances were dissolved in a concentration of 10⁻² M in DMSO.Further dilution of these DMSO solutions took place in incubation buffer(50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4).

Membrane Preparation:

CHO-K1 cells with stably expressed human vasopressin V2 receptor (clone23) were harvested and homogenized in 50 mM Tris-HCl and in the presenceof protease inhibitors (Roche complete Mini #1836170) using a Polytronhomogenizer at intermediate setting for 2×10 seconds, and subsequentlycentrifuged at 40 000×g for 1 h. The membrane pellet was againhomogenized and centrifuged as described and subsequently taken up in 50mM Tris-HCl, pH 7.4, homogenized and stored in aliquots frozen in liquidnitrogen at −190° C.

Binding Assay:

The binding assay was carried out by the method based on that of Taharaet al. (Tahara A et al., Brit. J. Pharmacol. 125, 1463-1470 (1998)).

The incubation buffer was: 50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH 7.4.

In the assay mixture (250 μl), membranes (50 μg/ml protein in incubationbuffer) from CHO-K1 cells with stably expressed human V2 receptors (cellline hV2_23_CHO) were incubated with 1-2 nM ³H-AVP (8-Arg-vasopressin,PerkinElmer #18479) in incubation buffer (50 mM Tris, 10 mM MgCl₂, 0.1%BSA, pH 7.4) (total binding) or additionally with increasingconcentrations of test substance (displacement experiment). Thenonspecific binding was determined with 1 μM AVP (Bachem # H1780).Triplicate determinations were carried out.

After incubation (60 minutes at room temperature), the free radioligandwas filtered off by vacuum filtration (Skatron cell harvester 7000)through Wathman GF/B glass fiber filter mats, and the filters weretransferred into scintillation vials.

The liquid scintillation measurement took place in a model 2000 or2200CA Tricarb instrument (Packard). Conversion of the measured cpm intodpm was carried out with the aid of a standard quench series.

Analysis:

The binding parameters were calculated by nonlinear regression in SAS.The algorithms of the program operate in analogy to the LIGAND analysisprogram (Munson P J and Rodbard D, Analytical Biochem. 107, 220-239(1980)). The Kd of ³H-AVP for the recombinant hV2 receptors is 2.4 nMand was used to determine the Ki.

4. Oxytocin Receptor Binding Assay Substances:

The substances were dissolved in a concentration of 10⁻² M in DMSO anddiluted with incubation buffer (50 mM Tris, 10 mM MgCl₂, 0.1% BSA, pH7.4).

Cell Preparation:

Confluent HEK-293 cells with transiently expressing recombinant humanoxytocin receptors were centrifuged at 750×g at room temperature for 5minutes. The residue was taken up in ice-cold lysis buffer (50 mMTris-HCl, 10% glycerol, pH 7.4 and Roche complete protease inhibitor)and subjected to an osmotic shock at 4° C. for 20 minutes. The lyzedcells were then centrifuged at 750×g at 4° C. for 20 minutes, theresidue was taken up in incubation buffer, and aliquots of 10⁷ cells/mlwere prepared. The aliquots were frozen at −80° C. until used.

Binding Assay:

On the day of the experiment, the cells were thawed, diluted withincubation buffer and homogenized using a Multipette Combitip(Eppendorf, Hamburg). The reaction mixture of 0.250 ml was composed of 2to 5×10⁴ recombinant cells, 3-4 nM ³H-oxytocin (PerkinElmer, NET 858) inthe presence of test substance (inhibition plot) or only incubationbuffer (total binding). The nonspecific binding was determined with 10⁻⁶M oxytocin (Bachem AG, H2510). Triplicate determinations were set up.Bound and free radioligand were separated by filtration under vacuumwith Whatman GF/B glass fiber filters with the aid of a Skatron cellharvester 7000. The bound radioactivity was determined by liquidscintillation measurement in a Tricarb Beta counter, model 2000 or2200CA (Packard).

Analysis:

The binding parameters were calculated by nonlinear regression analysis(SAS) in analogy to the LIGAND program of Munson and Rodbard (AnalyticalBiochem 1980; 107: 220-239). The Kd of ³H-oxytocin for the recombinanthOT receptors is 7.6 nM and was used to determine the Ki.

5. Determination of the Microsomal Half-Life:

The metabolic stability of the compounds of the invention was determinedin the following assay.

The test substances were incubated in a concentration of 0.5 μM asfollows:

0.5 μM test substance are preincubated together with liver microsomesfrom different species (from rat, human or other species) (0.25 mg ofmicrosomal protein/ml) in 0.05 M potassium phosphate buffer of pH 7.4 inmicrotiter plates at 37° C. for 5 min. The reaction is started by addingNADPH (1 mg/mL). After 0, 5, 10, 15, 20 and 30 min, 50 μl aliquots areremoved, and the reaction is immediately stopped and cooled with thesame volume of acetonitrile. The samples are frozen until analyzed. Theremaining concentration of undegraded test substance is determined byMSMS. The half-life (T½) is determined from the gradient of the signalof test substance/unit time plot, it being possible to calculate thehalf-life of the test substance, assuming first order kinetics, from thedecrease in the concentration of the compound with time. The microsomalclearance (mCl) is calculated from mCl=In2/T½/(content of microsomalprotein in mg/ml)×1000 [ml/min/mg] (modified from references: Di, TheSociety for Biomoleculur Screening, 2003, 453-462; Obach, D M D, 1999vol 27. N 11, 1350-1359).

6. Determination of the Plasma Protein Binding (PPB) by EquilibriumDialysis:

150 μl of rat or human plasma to which 1 or 10 μM of test substance wasadded is pipetted on one side of the 96-well dialysis chambers, and 150μl of PPS buffer are pipetted on the other side. The chambers areseparated by a dialysis membrane with a cut-off of 6-8000 daltons. The96-well dialysis chambers are covered and shaken gently overnight. Thenext morning, 10 μl of plasma are removed and diluted with 90 μl of PPSbuffer, and the protein is precipitated with 200 μl of acetonitrile. Theprecipitated protein is centrifuged down and 100 μl of the supernatantis used for the MSMS analysis. 100 μl are removed from the buffer sidefor MSMS analysis. See also the following reference: Banker, Journal ofPharmaceutical Sciences Vol, 92, 5, 967-974, 2003.

7. Methods for In Vitro Determination of the Cytochrome P450 (CYP)Inhibition Luminescent Substrates for 2C9 and 3A4:

0.4 mg/ml human liver microsomes are preincubated with the testsubstances to be investigated (0-20 μM), the CYP-specific substrates, in0.05 M potassium phosphate buffer of pH 7.4 at 37° C. for 10 min. TheCyp-specific substrate for CYP 2C9 is luciferin H, and for CYP 3A4 isluciferin BE. The reaction is started by adding NADPH. After incubationat RT for 30 min, the luciferin detection reagent is added, and theresulting luminescence signal is measured (modified from reference:Promega, Technical Bulletin P450-GLO™ Assays).

Midazolam CYP 3A4 Time-Dependent Inhibition

The assay consists of 2 parts. Firstly, the test substance ispreincubated with the liver microsomes (with NADPH=preincubation, thenaddition of the substrate; in the second part the substrate and the testsubstance are added simultaneously=coincubation.

Preincubation:

0.05 mg/ml microsomal protein (human liver microsomes) are preincubatedwith 0-10 μM (or 50 μM) test substance in 50 mM potassium phosphatebuffer for 5 min. The reaction is started with NADPH. After 30 min 4 μMmidazolam (final concentration) are added, and incubation is continuedfor 10 min. 75 μl of the reaction solution are removed after 10 min, andstopped with 150 μl of acetonitrile solution.

Coincubation:

0.05 mg/ml microsomal protein (human liver microsomes) are preincubatedwith 4 μM midazolam (final concentration) and 0-10 μM (or 50 μM) testsubstance in 50 mM potassium phosphate buffer for 5 min. The reaction isstarted with NADPH. 75 μl of the reaction solution are removed after 10min and stopped with 150 μl of acetonitrile solution. The samples arefrozen until the MSMS analysis (modified from references: Obdach,Journal of Pharmacology & Experimental Therapeutics, Vol 316, 1,336-348, 2006; Walsky, Drug Metabolism and Disposition Vol 32, 6,647-660, 2004).

8. Method for Determining the Solubility in Water (in Mg/Ml)

The solubility in water of the compounds of the invention can bedetermined for example by the so-called shake flask method (as specifiedin ASTM International: E 1148-02, Standard test methods for measurementof aqueous solubility, Book of Standards Volume 11.05.). This entails anexcess of the solid compound being put into a buffer solution with aparticular pH (for example phosphate buffer of pH 7.4), and theresulting mixture being shaken or stirred until equilibrium has been setup (typically 24 or 48 hours, sometimes even up to 7 days). Theundissolved solid is then removed by filtration or centrifugation, andthe concentration of the dissolved compound is determined by UVspectroscopy or high pressure liquid chromatography (HPLC) by means ofan appropriate calibration plot.

9. Results

The results of the receptor binding investigations are expressed asreceptor binding constants [K_(i)(V1b), K_(i)(V1a), K_(i)(V2),K_(i)(OT)]. The results of the investigation of the metabolic stabilityare indicated as microsomal clearance (mCl).

The compounds of the invention show very high affinities for the V1breceptor in these assays (maximally 100 nM, or maximally 50 nM,frequently <10 nM). The compounds also show high selectivities vis-à-visthe V1a, V2 and/or OT receptor and a good metabolic stability, measuredas microsomal clearance.

The results are listed in table 3.

TABLE 3 Human microsomal K_(i)(h-V1b)* K_(i)(h-V1a)/ K_(i)(h-OT)/clearance Example [nM] K_(i)(h-V1b)* K_(i)(h-V1b)* [μl min⁻¹ mg⁻¹]  1+++ +++ +++ +  2 +++ +++ +++ +  2B +++ +++ +++ +  4 +++ +++ +++ +++  4B+++ +++ +++ +++  5 +++ +++ ++ + 10 +++ +++ +++ +++ 25 +++ +++ + ++ 28 ++++ +++ +++ 32 ++ ++ +++ + 35 +++ ++ ++ + 37 +++ +++ +++ + 40 +++ ++ +++++ 55 +++ ++ + + K_(i)(V1a)/ K_(i)(OT)/ Human microsomal Key: K_(i)(V1b)K_(i)(V1b) K_(i)(V1b) clearance + >50-100 nM  15-25  15-25 >75-200 μlmin⁻¹ mg⁻¹ ++ 10-50 nM >25-75 >25-45 50-75 μl min⁻¹ mg⁻¹ +++ <10nM >75 >45 <50 μl min⁻¹ mg⁻¹ *h = human

1. A compound of the formula I

in which R¹ is hydrogen, methoxy or ethoxy; R² is hydrogen or methoxy;R³ is hydrogen, methyl, ethyl, n-propyl or isopropyl; X¹ and X² are N orCH, with the proviso that X¹ and X² are not simultaneously N; and theirpharmaceutically acceptable salts and prodrugs thereof.
 2. A compound asclaimed in claim 1, in which R¹ is hydrogen or methoxy.
 3. A compound asclaimed in any of the preceding claims, in which R³ is hydrogen, methylor ethyl.
 4. A compound as claimed in any of the preceding claims, inwhich X¹ is N and X² is CH.
 5. A compound as claimed in any of claims 1to 3, in which X¹ is CH and X² is N.
 6. A compound as claimed in any ofclaims 1 to 3, in which X¹ is CH and X² is CH.
 7. A compound as claimedin any of claims 1 to 3 and 5, in which R¹ is methoxy; R² is methoxy; R³is methyl or ethyl; X¹ is CH; and X² is N.
 8. A compound as claimed inany of claims 1 to 3 and 5, in which R¹ is methoxy; R² is H; R³ ismethyl or ethyl; X¹ is CH; and X² is N.
 9. A compound as claimed in anyof claims 1 to 3 and 5, in which R¹ is H; R² is methoxy; R³ is methyl orethyl; X¹ is CH; and X² is N.
 10. A compound as claimed in any of claims1 to 3 and 5, in which R¹ is H; R² is H; R³ is methyl or ethyl; X¹ isCH; and X² is N.
 11. A compound as claimed in any of claims 1 to 4, inwhich R¹ is methoxy; R² is methoxy; R³ is methyl or ethyl; X¹ is N; andX² is CH.
 12. A compound as claimed in any of claims 1 to 4, in which R¹is methoxy; R² is H; R³ is methyl or ethyl; X¹ is N; and X² is CH.
 13. Acompound as claimed in any of claims 1 to 4, in which R¹ is H; R² ismethoxy; R³ is methyl or ethyl; X¹ is N; and X² is CH.
 14. A compound asclaimed in any of claims 1 to 4, in which R¹ is H; R² is H; R³ is methylor ethyl; X¹ is N; and X² is CH.
 15. A compound as claimed in any of thepreceding claims, which is the (−) enantiomer in an enantiomeric purityof at least 50% ee.
 16. A compound as claimed in claim 15, where the (−)enantiomer has an enantiomeric purity of at least 90% ee.
 17. A compoundas claimed in any of claims 1 to 14, which is the racemate.
 18. Apharmaceutical composition comprising at least one compound of theformula I as defined in any of the preceding claims and/or at least onepharmaceutically acceptable salt or prodrug thereof and at least onepharmaceutically acceptable carrier.
 19. The use of compounds of theformula I as defined in any of claims 1 to 17 or of pharmaceuticallyacceptable salts or prodrugs thereof for the manufacture of a medicamentfor the treatment and/or prophylaxis of vasopressin-dependent diseases.20. The use of compounds of the formula I as defined in any of claims 1to 17 or of pharmaceutically acceptable salts or prodrugs thereof forthe manufacture of a medicament for the treatment and/or prophylaxis ofdiseases selected from diabetes, insulin resistance, nocturnal enuresis,incontinence and diseases in which impairments of blood clotting occur,and/or for delaying micturition.
 21. The use of compounds of the formulaI as defined in any of claims 1 to 17 or of pharmaceutically acceptablesalts or prodrugs thereof for the manufacture of a medicament for thetreatment and/or prophylaxis of diseases selected from hypertension,pulmonary hypertension, heart failure, myocardial infarction, coronaryspasm, unstable angina, PTCA (percutaneous transluminal coronaryangioplasty), ischemias of the heart, impairments of the renal system,edemas, renal vasospasm, necrosis of the renal cortex, hyponatremia,hypokalemia, Schwartz-Bartter syndrome, impairments of thegastrointestinal tract, gastritic vasospasm, hepatocirrhosis, gastricand intestinal ulcers, emesis, emesis occurring during chemotherapy, andtravel sickness.
 22. The use of compounds of the formula I as defined inany of claims 1 to 17 or of pharmaceutically acceptable salts orprodrugs thereof for the manufacture of a medicament for the treatmentand/or prophylaxis of diseases selected from affective disorders. 23.The use of compounds of the formula I as defined in any of claims 1 to17 or of pharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofdiseases selected from anxiety disorders and stress-dependent anxietydisorders.
 24. The use of compounds of the formula I as defined in anyof claims 1 to 17 or of pharmaceutically acceptable salts or prodrugsthereof for the manufacture of a medicament for the treatment and/orprophylaxis of diseases selected from memory impairments and Alzheimer'sdisease.
 25. The use of compounds of the formula I as defined in any ofclaims 1 to 17 or of pharmaceutically acceptable salts or prodrugsthereof for the manufacture of a medicament for the treatment and/orprophylaxis of diseases selected from psychoses and psychotic disorders.26. The use of compounds of the formula I as defined in any of claims 1to 17 or of pharmaceutically acceptable salts or prodrugs thereof forthe manufacture of a medicament for the treatment and/or prophylaxis ofdiseases selected from Cushing's syndrome and other stress-dependentdiseases.
 27. The use of compounds of the formula I as defined in any ofclaims 1 to 17 or of pharmaceutically acceptable salts or prodrugsthereof for the manufacture of a medicament for the treatment and/orprophylaxis of diseases selected from sleep disorders.
 28. The use ofcompounds of the formula I as defined in any of claims 1 to 17 or ofpharmaceutically acceptable salts or prodrugs thereof for themanufacture of a medicament for the treatment and/or prophylaxis ofdiseases selected from depressive disorders.
 29. The use as claimed inclaim 28 for the treatment and/or prophylaxis of childhood onset mooddisorders.
 30. The use of compounds of the formula I as defined in anyof claims 1 to 17 or of pharmaceutically acceptable salts or prodrugsthereof for the manufacture of a medicament for the treatment and/orprophylaxis of vasomotor symptoms and/or thermoregulatory dysfunctions.31. The use of compounds of the formula I as defined in any of claims 1to 17 or of pharmaceutically acceptable salts or prodrugs thereof forthe manufacture of a medicament for the treatment and/or prophylaxis ofdrug or pharmaceutical dependencies and/or dependencies mediated byother factors; of stress caused by withdrawal of one or more factorsmediating the dependence; and/or of stress-induced relapses into drug orpharmaceutical dependencies and/or dependencies mediated by otherfactors.
 32. The use of compounds of the formula I as defined in any ofclaims 1 to 17 or of pharmaceutically acceptable salts or prodrugsthereof for the manufacture of a medicament for the treatment and/orprophylaxis of diseases selected from schizophrenia and psychosis.
 33. Amethod for treating disorders defined as in any of claims 19 to 32, inwhich an effective amount of at least one compound of the formula I asdefined in any of claims 1 to 17 or of at least one pharmaceuticallyacceptable salt or a prodrug thereof or of a pharmaceutical compositionas claimed in claim 18 is administered to a patient.